What is meant by 'fixing' of an antigen presenting cell?

What is meant by 'fixing' of an antigen presenting cell?

We are searching data for your request:

Forums and discussions:
Manuals and reference books:
Data from registers:
Wait the end of the search in all databases.
Upon completion, a link will appear to access the found materials.

Can someone please explain what does 'fixing' of an antigen presenting cell mean?

A. processed foreign antigens from proteasomes.
B. processed self-antigens from phagolysosome.
C. antibodies.
D. T cell antigens.

A. processed self-antigens from proteasomes.
B. processed foreign antigens from phagolysosomes.
C. antibodies.
D. T cell receptors.

Which type of antigen-presenting molecule is found on all nucleated cells?

C. antibodies
D. B-cell receptors

Which type of antigen-presenting molecule is found only on macrophages, dendritic cells, and B cells?

C. T-cell receptors
D. B-cell receptors

Data availability

All data generated and supporting the findings of this study are available within the paper. The RNA-seq data have been deposited in the Gene Expression Ominbus accession number GSE137244 and GSE137396. The whole-exome sequencing data have been deposited in the NCBI Sequence Read Archive accession number PRJNA564395. TCGA data used are publicly available at the Genomic Data Commons portal ( Source data are available for this paper. All other data supporting the findings of this study are available from the corresponding author on reasonable request.


Steinman, R. M. Decisions about dendritic cells: past, present, and future. Annu. Rev. Immunol. 30, 1–22 (2012).

Becher, B. et al. High-dimensional analysis of the murine myeloid cell system. Nat. Immunol. 15, 1181–1189 (2014).

Murphy, T. L. et al. Transcriptional control of dendritic cell development. Annu. Rev. Immunol. 34, 93–119 (2016).

Ginhoux, F. & Jung, S. Monocytes and macrophages: developmental pathways and tissue homeostasis. Nat. Rev. Immunol. 14, 392–404 (2014).

Guilliams, M. et al. Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny. Nat. Rev. Immunol. 14, 571–578 (2014).

Guilliams, M. & van de Laar, L. A hitchhiker's guide to myeloid cell subsets: practical implementation of a novel mononuclear phagocyte classification system. Front. Immunol. 6, 406 (2015).

Reynolds, G. & Haniffa, M. Human and mouse mononuclear phagocyte networks: a tale of two species? Front. Immunol. 6, 330 (2015).

Merad, M., Sathe, P., Helft, J., Miller, J. & Mortha, A. The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu. Rev. Immunol. 31, 563–604 (2013).

Mildner, A. & Jung, S. Development and function of dendritic cell subsets. Immunity 40, 642–656 (2014).

Ohl, L. et al. CCR7 governs skin dendritic cell migration under inflammatory and steady-state conditions. Immunity 21, 279–288 (2004).

Tal, O. et al. DC mobilization from the skin requires docking to immobilized CCL21 on lymphatic endothelium and intralymphatic crawling. J. Exp. Med. 208, 2141–2153 (2011).

Weber, M. et al. Interstitial dendritic cell guidance by haptotactic chemokine gradients. Science 339, 328–332 (2013). This study identified endogenous gradients of immobilized CCL21 within the skin that guide migrating DCs towards and into initial lymphatics by means of CCR7-dependent haptotactic directional cues.

Pflicke, H. & Sixt, M. Preformed portals facilitate dendritic cell entry into afferent lymphatic vessels. J. Exp. Med. 206, 2925–2935 (2009).

Rescigno, M., Martino, M., Sutherland, C. L., Gold, M. R. & Ricciardi-Castagnoli, P. Dendritic cell survival and maturation are regulated by different signaling pathways. J. Exp. Med. 188, 2175–2180 (1998).

Krappmann, D. et al. The IκB kinase complex and NF-κB act as master regulators of lipopolysaccharide-induced gene expression and control subordinate activation of AP-1. Mol. Cell. Biol. 24, 6488–6500 (2004).

Baratin, M. et al. Homeostatic NF-κB signaling in steady-state migratory dendritic cells regulates immune homeostasis and tolerance. Immunity 42, 627–639 (2015).

Braun, A. et al. Afferent lymph-derived T cells and DCs use different chemokine receptor CCR7-dependent routes for entry into the lymph node and intranodal migration. Nat. Immunol. 12, 879–887 (2011).

Ulvmar, M. H. et al. The atypical chemokine receptor CCRL1 shapes functional CCL21 gradients in lymph nodes. Nat. Immunol. 15, 623–630 (2014). This manuscript shows the active formation of a chemokine gradient shaped by an atypical chemokine receptor.

Lämmermann, T. et al. Rapid leukocyte migration by integrin-independent flowing and squeezing. Nature 453, 51–55 (2008).

Wendland, M. et al. Lymph node T cell homeostasis relies on steady state homing of dendritic cells. Immunity 35, 945–957 (2011).

Qu, C. et al. Role of CCR8 and other chemokine pathways in the migration of monocyte-derived dendritic cells to lymph nodes. J. Exp. Med. 200, 1231–1241 (2004).

Sixt, M. et al. The conduit system transports soluble antigens from the afferent lymph to resident dendritic cells in the T cell area of the lymph node. Immunity 22, 19–29 (2005).

Liu, K. et al. In vivo analysis of dendritic cell development and homeostasis. Science 324, 392–397 (2009).

Seth, S. et al. CCR7 essentially contributes to the homing of plasmacytoid dendritic cells to lymph nodes under steady-state as well as inflammatory conditions. J. Immunol. 186, 3364–3372 (2011).

Gatto, D. et al. The chemotactic receptor EBI2 regulates the homeostasis, localization and immunological function of splenic dendritic cells. Nat. Immunol. 14, 446–453 (2013).

Yi, T. & Cyster, J. G. EBI2-mediated bridging channel positioning supports splenic dendritic cell homeostasis and particulate antigen capture. eLife 2, e00757 (2013).

León, B. et al. Regulation of TH2 development by CXCR5 + dendritic cells and lymphotoxin-expressing B cells. Nat. Immunol. 13, 681–690 (2012).

Woodruff, M. C. et al. Trans-nodal migration of resident dendritic cells into medullary interfollicular regions initiates immunity to influenza vaccine. J. Exp. Med. 211, 1611–1621 (2014).

Gonzalez, S. F. et al. Capture of influenza by medullary dendritic cells via SIGN-R1 is essential for humoral immunity in draining lymph nodes. Nat. Immunol. 11, 427–434 (2010).

Tan, S.-Y., Roediger, B. & Weninger, W. The role of chemokines in cutaneous immunosurveillance. Immunol. Cell Biol. 93, 337–346 (2015).

Malissen, B., Tamoutounour, S. & Henri, S. The origins and functions of dendritic cells and macrophages in the skin. Nat. Rev. Immunol. 14, 417–428 (2014).

Wang, Y. et al. IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia. Nat. Immunol. 13, 753–760 (2012).

Kaplan, D. H., Jenison, M. C., Saeland, S., Shlomchik, W. D. & Shlomchik, M. J. Epidermal Langerhans cell-deficient mice develop enhanced contact hypersensitivity. Immunity 23, 611–620 (2005).

Ginhoux, F. et al. Langerhans cells arise from monocytes in vivo. Nat. Immunol. 7, 265–273 (2006).

Nagao, K. et al. Stress-induced production of chemokines by hair follicles regulates the trafficking of dendritic cells in skin. Nat. Immunol. 13, 744–752 (2012).

Bobr, A. et al. Autocrine/paracrine TGF-β1 inhibits Langerhans cell migration. Proc. Natl Acad. Sci. USA 109, 10492–10497 (2012).

Kissenpfennig, A. et al. Dynamics and function of Langerhans cells in vivo: dermal dendritic cells colonize lymph node areas distinct from slower migrating Langerhans cells. Immunity 22, 643–654 (2005).

Shklovskaya, E. et al. Langerhans cells are precommitted to immune tolerance induction. Proc. Natl Acad. Sci. USA 108, 18049–18054 (2011).

Flacher, V. et al. Murine Langerin + dermal dendritic cells prime CD8 + T cells while Langerhans cells induce cross-tolerance. EMBO Mol. Med. 6, 1191–1204 (2014).

Gomez de Agüero, M. et al. Langerhans cells protect from allergic contact dermatitis in mice by tolerizing CD8 + T cells and activating Foxp3 + regulatory T cells. J. Clin. Invest. 122, 1700–1711 (2012).

Gaiser, M. R. et al. Cancer-associated epithelial cell adhesion molecule (EpCAM CD326) enables epidermal Langerhans cell motility and migration in vivo. Proc. Natl Acad. Sci. USA 109, E889–E897 (2012).

Kautz-Neu, K. et al. Langerhans cells are negative regulators of the anti-Leishmania response. J. Exp. Med. 208, 885–891 (2011).

Igyártó, B. Z. et al. Skin-resident murine dendritic cell subsets promote distinct and opposing antigen-specific T helper cell responses. Immunity 35, 260–272 (2011).

Schlitzer, A. et al. Identification of cDC1- and cDC2-committed DC progenitors reveals early lineage priming at the common DC progenitor stage in the bone marrow. Nat. Immunol. 16, 718–728 (2015).

Henri, S. et al. CD207 + CD103 + dermal dendritic cells cross-present keratinocyte-derived antigens irrespective of the presence of Langerhans cells. J. Exp. Med. 207, 189–206 (2010).

Bedoui, S. et al. Cross-presentation of viral and self antigens by skin-derived CD103 + dendritic cells. Nat. Immunol. 10, 488–495 (2009).

Murphy, T. L., Tussiwand, R. & Murphy, K. M. Specificity through cooperation: BATF–IRF interactions control immune-regulatory networks. Nat. Rev. Immunol. 13, 499–509 (2013).

Naik, S. et al. Commensal–dendritic-cell interaction specifies a unique protective skin immune signature. Nature 520, 104–108 (2015).

Kitajima, M. & Ziegler, S. F. Cutting edge: identification of the thymic stromal lymphopoietin-responsive dendritic cell subset critical for initiation of type 2 contact hypersensitivity. J. Immunol. 191, 4903–4907 (2013).

Stutte, S. et al. Requirement of CCL17 for CCR7- and CXCR4-dependent migration of cutaneous dendritic cells. Proc. Natl Acad. Sci. USA 107, 8736–8741 (2010).

Tamoutounour, S. et al. Origins and functional specialization of macrophages and of conventional and monocyte-derived dendritic cells in mouse skin. Immunity 39, 925–938 (2013).

Mollah, S. A. et al. Flt3L dependence helps define an uncharacterized subset of murine cutaneous dendritic cells. J. Invest. Dermatol. 134, 1265–1275 (2014).

Pascale, F. et al. Plasmacytoid dendritic cells migrate in afferent skin lymph. J. Immunol. 180, 5963–5972 (2008).

Sisirak, V. et al. CCR6/CCR10-mediated plasmacytoid dendritic cell recruitment to inflamed epithelia after instruction in lymphoid tissues. Blood 118, 5130–5140 (2011).

Davalos-Misslitz, A. C. M. et al. Generalized multi-organ autoimmunity in CCR7-deficient mice. Eur. J. Immunol. 37, 613–622 (2007).

Bajaña, S., Roach, K., Turner, S., Paul, J. & Kovats, S. IRF4 promotes cutaneous dendritic cell migration to lymph nodes during homeostasis and inflammation. J. Immunol. 189, 3368–3377 (2012).

Yabe, R. et al. CCR8 regulates contact hypersensitivity by restricting cutaneous dendritic cell migration to the draining lymph nodes. Int. Immunol. 27, 169–181 (2015).

Sawada, Y. et al. Resolvin E1 inhibits dendritic cell migration in the skin and attenuates contact hypersensitivity responses. J. Exp. Med. 212, 1921–1930 (2015). Here the authors demonstrate that resolvin E1, a lipid mediator derived from ω3 polyunsaturated fatty acids, impairs DC motility in the skin.

Tomura, M. et al. Tracking and quantification of dendritic cell migration and antigen trafficking between the skin and lymph nodes. Sci. Rep. 4, 6030 (2014).

Girard, J.-P., Moussion, C. & Förster, R. HEVs, lymphatics and homeostatic immune cell trafficking in lymph nodes. Nat. Rev. Immunol. 12, 762–773 (2012).

Cook, D. N. et al. CCR6 mediates dendritic cell localization, lymphocyte homeostasis, and immune responses in mucosal tissue. Immunity 12, 495–503 (2000).

Shreedhar, V. K., Kelsall, B. L. & Neutra, M. R. Cholera toxin induces migration of dendritic cells from the subepithelial dome region to T − and B-cell areas of Peyer's patches. Infect. Immun. 71, 504–509 (2003).

Salazar-Gonzalez, R. M. et al. CCR6-mediated dendritic cell activation of pathogen-specific T cells in Peyer's patches. Immunity 24, 623–632 (2006).

Lopez-Guerrero, D. V. et al. Rotavirus infection activates dendritic cells from Peyer's patches in adult mice. J. Virol. 84, 1856–1866 (2010).

Cerovic, V. et al. Intestinal CD103 − dendritic cells migrate in lymph and prime effector T cells. Mucosal Immunol. 6, 104–113 (2013).

Pabst, O. et al. Adaptation of solitary intestinal lymphoid tissue in response to microbiota and chemokine receptor CCR7 signaling. J. Immunol. 177, 6824–6832 (2006).

Schulz, O. et al. Intestinal CD103 + , but not CX3CR1 + , antigen sampling cells migrate in lymph and serve classical dendritic cell functions. J. Exp. Med. 206, 3101–3114 (2009).

Yrlid, U. et al. Regulation of intestinal dendritic cell migration and activation by plasmacytoid dendritic cells, TNF-α and type 1 IFNs after feeding a TLR7/8 ligand. J. Immunol. 176, 5205–5212 (2006).

Persson, E. K. et al. IRF4 transcription-factor-dependent CD103 + CD11b + dendritic cells drive mucosal T helper 17 cell differentiation. Immunity 38, 958–969 (2013).

Coombes, J. L. et al. A functionally specialized population of mucosal CD103 + DCs induces Foxp3 + regulatory T cells via a TGF-β and retinoic acid-dependent mechanism. J. Exp. Med. 204, 1757–1764 (2007).

Sun, C.-M. et al. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J. Exp. Med. 204, 1775–1785 (2007).

Johansson-Lindbom, B. et al. Functional specialization of gut CD103 + dendritic cells in the regulation of tissue-selective T cell homing. J. Exp. Med. 202, 1063–1073 (2005).

Jaensson, E. et al. Small intestinal CD103 + dendritic cells display unique functional properties that are conserved between mice and humans. J. Exp. Med. 205, 2139–2149 (2008).

Scott, C. L. et al. CCR2 + CD103 − intestinal dendritic cells develop from DC-committed precursors and induce interleukin-17 production by T cells. Mucosal Immunol. 8, 327–339 (2015).

Diehl, G. E. et al. Microbiota restricts trafficking of bacteria to mesenteric lymph nodes by CX3CR1 hi cells. Nature 494, 116–120 (2013).

Worbs, T. et al. Oral tolerance originates in the intestinal immune system and relies on antigen carriage by dendritic cells. J. Exp. Med. 203, 519–527 (2006).

Farache, J. et al. Luminal bacteria recruit CD103 + dendritic cells into the intestinal epithelium to sample bacterial antigens for presentation. Immunity 38, 581–595 (2013).

Niess, J. H. & Reinecker, H.-C. Lamina propria dendritic cells in the physiology and pathology of the gastrointestinal tract. Curr. Opin. Gastroenterol. 21, 687–691 (2005).

McDole, J. R. et al. Goblet cells deliver luminal antigen to CD103 + dendritic cells in the small intestine. Nature 483, 345–349 (2012).

Arques, J. L. et al. Salmonella induces flagellin- and MyD88-dependent migration of bacteria-capturing dendritic cells into the gut lumen. Gastroenterology 137, 579–587. e2 (2009).

Yrlid, U. et al. Plasmacytoid dendritic cells do not migrate in intestinal or hepatic lymph. J. Immunol. 177, 6115–6121 (2006).

Wendland, M. et al. CCR9 is a homing receptor for plasmacytoid dendritic cells to the small intestine. Proc. Natl Acad. Sci. USA 104, 6347–6352 (2007).

Goubier, A. et al. Plasmacytoid dendritic cells mediate oral tolerance. Immunity 29, 464–475 (2008).

Mizuno, S. et al. CCR9 + plasmacytoid dendritic cells in the small intestine suppress development of intestinal inflammation in mice. Immunol. Lett. 146, 64–69 (2012).

Baumgart, D. C. et al. Aberrant plasmacytoid dendritic cell distribution and function in patients with Crohn's disease and ulcerative colitis. Clin. Exp. Immunol. 166, 46–54 (2011).

Kwa, S. et al. Plasmacytoid dendritic cells are recruited to the colorectum and contribute to immune activation during pathogenic SIV infection in rhesus macaques. Blood 118, 2763–2773 (2011).

Bain, C. C. et al. Resident and pro-inflammatory macrophages in the colon represent alternative context-dependent fates of the same Ly6C hi monocyte precursors. Mucosal Immunol. 6, 498–510 (2013).

Tamoutounour, S. et al. CD64 distinguishes macrophages from dendritic cells in the gut and reveals the Th1-inducing role of mesenteric lymph node macrophages during colitis. Eur. J. Immunol. 42, 3150–3166 (2012).

Dunay, I. R. et al. Gr1 + inflammatory monocytes are required for mucosal resistance to the pathogen Toxoplasma gondii. Immunity 29, 306–317 (2008).

Schreiber, H. A. et al. Intestinal monocytes and macrophages are required for T cell polarization in response to Citrobacter rodentium. J. Exp. Med. 210, 2025–2039 (2013).

Rivollier, A., He, J., Kole, A., Valatas, V. & Kelsall, B. L. Inflammation switches the differentiation program of Ly6C hi monocytes from antiinflammatory macrophages to inflammatory dendritic cells in the colon. J. Exp. Med. 209, 139–155 (2012).

Zigmond, E. et al. Ly6C hi monocytes in the inflamed colon give rise to proinflammatory effector cells and migratory antigen-presenting cells. Immunity 37, 1076–1090 (2012).

Siddiqui, K. R. R., Laffont, S. & Powrie, F. E-Cadherin marks a subset of inflammatory dendritic cells that promote T cell-mediated colitis. Immunity 32, 557–567 (2010).

Langlet, C. et al. CD64 expression distinguishes monocyte-derived and conventional dendritic cells and reveals their distinct role during intramuscular immunization. J. Immunol. 188, 1751–1760 (2012).

Esterházy, D. et al. Classical dendritic cells are required for dietary antigen-mediated induction of peripheral Treg cells and tolerance. Nat. Immunol. 17, 545–555 (2016).

Rimoldi, M. et al. Intestinal immune homeostasis is regulated by the crosstalk between epithelial cells and dendritic cells. Nat. Immunol. 6, 507–514 (2005).

Jaensson-Gyllenbäck, E. et al. Bile retinoids imprint intestinal CD103 + dendritic cells with the ability to generate gut-tropic T cells. Mucosal Immunol. 4, 438–447 (2011).

McDonald, K. G. et al. Epithelial expression of the cytosolic retinoid chaperone cellular retinol binding protein II is essential for in vivo imprinting of local gut dendritic cells by lumenal retinoids. Am. J. Pathol. 180, 984–997 (2012).

Laffont, S., Siddiqui, K. R. R. & Powrie, F. Intestinal inflammation abrogates the tolerogenic properties of MLN CD103 + dendritic cells. Eur. J. Immunol. 40, 1877–1883 (2010).

Zhang, Z. et al. Peripheral lymphoid volume expansion and maintenance are controlled by gut microbiota via RALDH + dendritic cells. Immunity 44, 330–342 (2016). This study shows that neonatal DCs in the gut respond to microbial colonization and migrate to cutaneous lymph nodes, where they instruct HEV maturation for the initiation of L-selectin-based homing of lymphocytes and lymph node cellularity increase.

Macpherson, A. J. & Uhr, T. Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria. Science 303, 1662–1665 (2004).

Goto, Y. et al. Segmented filamentous bacteria antigens presented by intestinal dendritic cells drive mucosal Th17 cell differentiation. Immunity 40, 594–607 (2014).

Round, J. L. & Mazmanian, S. K. Inducible Foxp3 + regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc. Natl Acad. Sci. USA 107, 12204–12209 (2010).

Fonseca, D. M. da et al. Microbiota-dependent sequelae of acute infection compromise tissue-specific immunity. Cell 163, 354–366 (2015).

Voedisch, S. et al. Mesenteric lymph nodes confine dendritic cell-mediated dissemination of Salmonella enterica serovar Typhimurium and limit systemic disease in mice. Infect. Immun. 77, 3170–3180 (2009).

Uematsu, S. et al. Detection of pathogenic intestinal bacteria by Toll-like receptor 5 on intestinal CD11c + lamina propria cells. Nat. Immunol. 7, 868–874 (2006).

del Rio, M.-L., Rodriguez-Barbosa, J.-I., Kremmer, E. & Förster, R. CD103 − and CD103 + bronchial lymph node dendritic cells are specialized in presenting and cross-presenting innocuous antigen to CD4 + and CD8 + T cells. J. Immunol. 178, 6861–6866 (2007).

Hintzen, G. et al. Induction of tolerance to innocuous inhaled antigen relies on a CCR7-dependent dendritic cell-mediated antigen transport to the bronchial lymph node. J. Immunol. 177, 7346–7354 (2006).

Kandasamy, M. et al. Complement mediated signaling on pulmonary CD103 + dendritic cells is critical for their migratory function in response to influenza infection. PLoS Pathog. 9, e1003115 (2013).

Jakubzick, C., Tacke, F., Llodra, J., van Rooijen, N. & Randolph, G. J. Modulation of dendritic cell trafficking to and from the airways. J. Immunol. 176, 3578–3584 (2006).

Otero, K. et al. Nonredundant role of CCRL2 in lung dendritic cell trafficking. Blood 116, 2942–2949 (2010).

Idzko, M. et al. Local application of FTY720 to the lung abrogates experimental asthma by altering dendritic cell function. J. Clin. Invest. 116, 2935–2944 (2006).

Hammad, H. et al. Prostaglandin D2 inhibits airway dendritic cell migration and function in steady state conditions by selective activation of the D prostanoid receptor 1. J. Immunol. 171, 3936–3940 (2003).

Zhao, J. J., Zhao, J. J., Legge, K. & Perlman, S. Age-related increases in PGD2 expression impair respiratory DC migration, resulting in diminished T cell responses upon respiratory virus infection in mice. J. Clin. Invest. 121, 4921–4930 (2011).

Le Nouën, C. et al. Low CCR7-mediated migration of human monocyte derived dendritic cells in response to human respiratory syncytial virus and human metapneumovirus. PLoS Pathog. 7, e1002105 (2011).

Ichinohe, T. et al. Microbiota regulates immune defense against respiratory tract influenza A virus infection. Proc. Natl Acad. Sci. USA 108, 5354–5359 (2011).

Pang, I. K., Ichinohe, T. & Iwasaki, A. IL-1R signaling in dendritic cells replaces pattern-recognition receptors in promoting CD8 + T cell responses to influenza A virus. Nat. Immunol. 14, 246–253 (2013).

Thornton, E. E. et al. Spatiotemporally separated antigen uptake by alveolar dendritic cells and airway presentation to T cells in the lung. J. Exp. Med. 209, 1183–1199 (2012).

Hashimoto, M. et al. TGF-β-dependent dendritic cell chemokinesis in murine models of airway disease. J. Immunol. 195, 1182–1190 (2015).

Kitamura, H. et al. Mouse and human lung fibroblasts regulate dendritic cell trafficking, airway inflammation, and fibrosis through integrin αvβ8-mediated activation of TGF-β. J. Clin. Invest. 121, 2863–2875 (2011).

Plantinga, M. et al. Conventional and monocyte-derived CD11b + dendritic cells initiate and maintain T helper 2 cell-mediated immunity to house dust mite allergen. Immunity 38, 322–335 (2013).

Hammad, H. et al. House dust mite allergen induces asthma via Toll-like receptor 4 triggering of airway structural cells. Nat. Med. 15, 410–416 (2009).

Willart, M. A. et al. Interleukin-1α controls allergic sensitization to inhaled house dust mite via the epithelial release of GM-CSF and IL-33. J. Exp. Med. 209, 1505–1517 (2012).

Upham, J. W. et al. Plasmacytoid dendritic cells during infancy are inversely associated with childhood respiratory tract infections and wheezing. J. Allergy Clin. Immunol. 124, 707–713. e2 (2009).

de Heer, H. J. et al. Essential role of lung plasmacytoid dendritic cells in preventing asthmatic reactions to harmless inhaled antigen. J. Exp. Med. 200, 89–98 (2004).

Kool, M. et al. An anti-inflammatory role for plasmacytoid dendritic cells in allergic airway inflammation. J. Immunol. 183, 1074–1082 (2009).

Lombardi, V., Speak, A. O., Kerzerho, J., Szely, N. & Akbari, O. CD8α + β − and CD8α + β + plasmacytoid dendritic cells induce Foxp3 + regulatory T cells and prevent the induction of airway hyper-reactivity. Mucosal Immunol. 5, 432–443 (2012).

Khare, A. et al. Cutting edge: inhaled antigen upregulates retinaldehyde dehydrogenase in lung CD103 + but not plasmacytoid dendritic cells to induce Foxp3 de novo in CD4 + T cells and promote airway tolerance. J. Immunol. 191, 25–29 (2013).

Vassallo, R. et al. Cigarette smoke promotes dendritic cell accumulation in COPD a Lung Tissue Research Consortium study. Respir. Res. 11, 45 (2010).

Demedts, I. K. et al. Accumulation of dendritic cells and increased CCL20 levels in the airways of patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 175, 998–1005 (2007).

Arellano-Orden, E. et al. Cigarette smoke decreases the maturation of lung myeloid dendritic cells. PLoS ONE 11, e0152737 (2016).

GeurtsvanKessel, C. H. et al. Clearance of influenza virus from the lung depends on migratory langerin + CD11b − but not plasmacytoid dendritic cells. J. Exp. Med. 205, 1621–1634 (2008).

Legge, K. L. & Braciale, T. J. Accelerated migration of respiratory dendritic cells to the regional lymph nodes is limited to the early phase of pulmonary infection. Immunity 18, 265–277 (2003).

Helft, J. et al. Cross-presenting CD103 + dendritic cells are protected from influenza virus infection. J. Clin. Invest. 122, 4037–4047 (2012).

Ho, A. W. S. et al. Lung CD103 + dendritic cells efficiently transport influenza virus to the lymph node and load viral antigen onto MHC class I for presentation to CD8 T cells. J. Immunol. 187, 6011–6021 (2011).

Guilliams, M., Lambrecht, B. N. & Hammad, H. Division of labor between lung dendritic cells and macrophages in the defense against pulmonary infections. Mucosal Immunol. 6, 464–473 (2013).

Ballesteros-Tato, A., León, B., Lund, F. E. & Randall, T. D. Temporal changes in dendritic cell subsets, cross-priming and costimulation via CD70 control CD8 + T cell responses to influenza. Nat. Immunol. 11, 216–224 (2010).

Lukens, M. V., Kruijsen, D., Coenjaerts, F. E. J., Kimpen, J. L. L. & van Bleek, G. M. Respiratory syncytial virus-induced activation and migration of respiratory dendritic cells and subsequent antigen presentation in the lung-draining lymph node. J. Virol. 83, 7235–7243 (2009).

Lin, K. L., Suzuki, Y., Nakano, H., Ramsburg, E. & Gunn, M. D. CCR2 + monocyte-derived dendritic cells and exudate macrophages produce influenza-induced pulmonary immune pathology and mortality. J. Immunol. 180, 2562–2572 (2008).

Nakano, H. et al. Migratory properties of pulmonary dendritic cells are determined by their developmental lineage. Mucosal Immunol. 6, 678–691 (2013).

Iijima, N., Mattei, L. M. & Iwasaki, A. Recruited inflammatory monocytes stimulate antiviral Th1 immunity in infected tissue. Proc. Natl Acad. Sci. USA 108, 284–289 (2011).

Cao, W. et al. Rapid differentiation of monocytes into type I IFN-producing myeloid dendritic cells as an antiviral strategy against influenza virus infection. J. Immunol. 189, 2257–2265 (2012).

Khader, S. A. et al. Interleukin 12p40 is required for dendritic cell migration and T cell priming after Mycobacterium tuberculosis infection. J. Exp. Med. 203, 1805–1815 (2006).

Shafiani, S., Tucker-Heard, G., Kariyone, A., Takatsu, K. & Urdahl, K. B. Pathogen-specific regulatory T cells delay the arrival of effector T cells in the lung during early tuberculosis. J. Exp. Med. 207, 1409–1420 (2010).

Curtis, J. et al. Susceptibility to tuberculosis is associated with variants in the ASAP1 gene encoding a regulator of dendritic cell migration. Nat. Genet. 47, 523–527 (2015).

Cleret, A. et al. Lung dendritic cells rapidly mediate anthrax spore entry through the pulmonary route. J. Immunol. 178, 7994–8001 (2007).

Medawar, P. B. Immunity to homologous grafted skin the fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye. Br. J. Exp. Pathol. 29, 58–69 (1948).

Bentivoglio, M. & Kristensson, K. Tryps and trips: cell trafficking across the 100-year-old blood-brain barrier. Trends Neurosci. 37, 325–333 (2014).

Ransohoff, R. M. & Engelhardt, B. The anatomical and cellular basis of immune surveillance in the central nervous system. Nat. Rev. Immunol. 12, 623–635 (2012).

Laman, J. D. & Weller, R. O. Drainage of cells and soluble antigen from the CNS to regional lymph nodes. J. Neuroimmune Pharmacol. 8, 840–856 (2013).

Louveau, A., Harris, T. H. & Kipnis, J. Revisiting the mechanisms of CNS immune privilege. Trends Immunol. 36, 569–577 (2015).

Aspelund, A. et al. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J. Exp. Med. 212, 991–999 (2015).

Louveau, A. et al. Structural and functional features of central nervous system lymphatic vessels. Nature 523, 337–341 (2015). Characterizing functional lymphatic vessels within the meninges, these two studies have shed new light on controversial questions of lymphatic drainage and, even more, cell-bound antigen-transport from the CNS, thus revisiting classic dogmas of CNS immune privilege.

Quintana, E. et al. DNGR-1 + dendritic cells are located in meningeal membrane and choroid plexus of the noninjured brain. Glia 63, 2231–2248 (2015).

Hatterer, E., Touret, M., Belin, M.-F., Honnorat, J. & Nataf, S. Cerebrospinal fluid dendritic cells infiltrate the brain parenchyma and target the cervical lymph nodes under neuroinflammatory conditions. PLoS ONE 3, e3321 (2008).

Jain, P., Coisne, C., Enzmann, G., Rottapel, R. & Engelhardt, B. α4β1 integrin mediates the recruitment of immature dendritic cells across the blood-brain barrier during experimental autoimmune encephalomyelitis. J. Immunol. 184, 7196–7206 (2010).

Paterka, M. et al. Gatekeeper role of brain antigen-presenting CD11c + cells in neuroinflammation. EMBO J. 35, 89–101 (2016).

Bartholomäus, I. et al. Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions. Nature 462, 94–98 (2009).

Clarkson, B. D. et al. CCR2-dependent dendritic cell accumulation in the central nervous system during early effector experimental autoimmune encephalomyelitis is essential for effector T cell restimulation in situ and disease progression. J. Immunol. 194, 531–541 (2015).

Ajami, B., Bennett, J. L., Krieger, C., McNagny, K. M. & Rossi, F. M. V. Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nat. Neurosci. 14, 1142–1149 (2011).

Yamasaki, R. et al. Differential roles of microglia and monocytes in the inflamed central nervous system. J. Exp. Med. 211, 1533–1549 (2014).

Duraes, F. V. et al. pDC therapy induces recovery from EAE by recruiting endogenous pDC to sites of CNS inflammation. J. Autoimmun. 67, 8–18 (2015).

Karni, A. et al. Innate immunity in multiple sclerosis: myeloid dendritic cells in secondary progressive multiple sclerosis are activated and drive a proinflammatory immune response. J. Immunol. 177, 4196–4202 (2006).

Thewissen, K. et al. Circulating dendritic cells of multiple sclerosis patients are proinflammatory and their frequency is correlated with MS-associated genetic risk factors. Mult. Scler. 20, 548–557 (2014).

Pashenkov, M. et al. Elevated expression of CCR5 by myeloid (CD11c + ) blood dendritic cells in multiple sclerosis and acute optic neuritis. Clin. Exp. Immunol. 127, 519–526 (2002).

Kivisäkk, P. et al. Expression of CCR7 in multiple sclerosis: implications for CNS immunity. Ann. Neurol. 55, 627–638 (2004).

Aung, L. L., Fitzgerald-Bocarsly, P., Dhib-Jalbut, S. & Balashov, K. Plasmacytoid dendritic cells in multiple sclerosis: chemokine and chemokine receptor modulation by interferon-beta. J. Neuroimmunol. 226, 158–164 (2010).

Mohammad, M. G. et al. Immune cell trafficking from the brain maintains CNS immune tolerance. J. Clin. Invest. 124, 1228–1241 (2014). Although its relevance in adult humans remains controversial, this study demonstrated that the RMS is an important migration pathway within the CNS parenchyma of rodents, not only for neurons repopulating the olfactory bulb but for CNS-emigrating DCs as well.

Ganguly, D., Haak, S., Sisirak, V. & Reizis, B. The role of dendritic cells in autoimmunity. Nat. Rev. Immunol. 13, 566–577 (2013).

Vitali, C. et al. Migratory, and not lymphoid-resident, dendritic cells maintain peripheral self-tolerance and prevent autoimmunity via induction of iTreg cells. Blood 120, 1237–1245 (2012).

Ochando, J. C. et al. Alloantigen-presenting plasmacytoid dendritic cells mediate tolerance to vascularized grafts. Nat. Immunol. 7, 652–662 (2006).

Bonasio, R. et al. Clonal deletion of thymocytes by circulating dendritic cells homing to the thymus. Nat. Immunol. 7, 1092–1100 (2006).

Hadeiba, H. et al. Plasmacytoid dendritic cells transport peripheral antigens to the thymus to promote central tolerance. Immunity 36, 438–450 (2012).

Page, G., Lebecque, S. & Miossec, P. Anatomic localization of immature and mature dendritic cells in an ectopic lymphoid organ: correlation with selective chemokine expression in rheumatoid synovium. J. Immunol. 168, 5333–5341 (2002).

Tarrant, T. K. et al. Decreased Th17 and antigen-specific humoral responses in CX3CR1-deficient mice in the collagen-induced arthritis model. Arthritis Rheum. 64, 1379–1387 (2012).

Yokoyama, W. et al. Abrogation of CC chemokine receptor 9 ameliorates collagen-induced arthritis of mice. Arthritis Res. Ther. 16, 445 (2014).

Li, X. et al. Apigenin, a potent suppressor of dendritic cell maturation and migration, protects against collagen-induced arthritis. J. Cell. Mol. Med. 20, 170–180 (2015).

Ibarra, J. M. et al. CD8α + dendritic cells improve collagen-induced arthritis in CC chemokine receptor (CCR)-2 deficient mice. Immunobiology 216, 971–978 (2011).

Han, Y. et al. FTY720 abrogates collagen-induced arthritis by hindering dendritic cell migration to local lymph nodes. J. Immunol. 195, 4126–4135 (2015).

Rowland, S. L. et al. Early, transient depletion of plasmacytoid dendritic cells ameliorates autoimmunity in a lupus model. J. Exp. Med. 211, 1977–1991 (2014).

Sisirak, V. et al. Genetic evidence for the role of plasmacytoid dendritic cells in systemic lupus erythematosus. J. Exp. Med. 211, 1969–1976 (2014).

Baccala, R. et al. Essential requirement for IRF8 and SLC15A4 implicates plasmacytoid dendritic cells in the pathogenesis of lupus. Proc. Natl Acad. Sci. USA 110, 2940–2945 (2013).

Blomberg, S. et al. Presence of cutaneous interferon-a producing cells in patients with systemic lupus erythematosus. Lupus 10, 484–490 (2001).

Khan, S. A. et al. Active systemic lupus erythematosus is associated with decreased blood conventional dendritic cells. Exp. Mol. Pathol. 95, 121–123 (2013).

Guiducci, C. et al. Autoimmune skin inflammation is dependent on plasmacytoid dendritic cell activation by nucleic acids via TLR7 and TLR9. J. Exp. Med. 207, 2931–2942 (2010).

Celhar, T. et al. RNA sensing by conventional dendritic cells is central to the development of lupus nephritis. Proc. Natl Acad. Sci. USA 112, E6195–E6204 (2015).

Hänsel, A. et al. Human 6-sulfo LacNAc (slan) dendritic cells have molecular and functional features of an important pro-inflammatory cell type in lupus erythematosus. J. Autoimmun. 40, 1–8 (2013).

Clatworthy, M. R. et al. Immune complexes stimulate CCR7-dependent dendritic cell migration to lymph nodes. Nat. Med. 20, 1458–1463 (2014). This paper reveals that immune complexes that are frequently found in autoimmune diseases induce DC mobilization thus potentially contributing to aggravation of disease.

Rodriguez-Pla, A. et al. IFN priming is necessary but not sufficient to turn on a migratory dendritic cell program in lupus monocytes. J. Immunol. 192, 5586–5598 (2014).

Perera, G. K., Di Meglio, P. & Nestle, F. O. Psoriasis. Annu. Rev. Pathol. 7, 385–422 (2012).

Guttman-Yassky, E., Nograles, K. E. & Krueger, J. G. Contrasting pathogenesis of atopic dermatitis and psoriasis — part II: immune cell subsets and therapeutic concepts. J. Allergy Clin. Immunol. 127, 1420–1432 (2011).

Wohn, C. et al. Langerin neg conventional dendritic cells produce IL-23 to drive psoriatic plaque formation in mice. Proc. Natl Acad. Sci. USA 110, 10723–10728 (2013).

Tortola, L. et al. Psoriasiform dermatitis is driven by IL-36-mediated DC-keratinocyte crosstalk. J. Clin. Invest. 122, 3965–3976 (2012).

Nestle, F. O. et al. Plasmacytoid predendritic cells initiate psoriasis through interferon-α production. J. Exp. Med. 202, 135–143 (2005).

Albanesi, C. et al. Chemerin expression marks early psoriatic skin lesions and correlates with plasmacytoid dendritic cell recruitment. J. Exp. Med. 206, 249–258 (2009).

Skrzeczyn´ska-Moncznik, J. et al. Potential role of chemerin in recruitment of plasmacytoid dendritic cells to diseased skin. Biochem. Biophys. Res. Commun. 380, 323–327 (2009).

Gonzalvo-Feo, S. et al. Endothelial cell-derived chemerin promotes dendritic cell transmigration. J. Immunol. 192, 2366–2373 (2014).

Terhorst, D. et al. Dynamics and transcriptomics of skin dendritic cells and macrophages in an imiquimod-induced, biphasic mouse model of psoriasis. J. Immunol. 195, 4953–4961 (2015).

Bosè, F. et al. Inhibition of CCR7/CCL19 axis in lesional skin is a critical event for clinical remission induced by TNF blockade in patients with psoriasis. Am. J. Pathol. 183, 413–421 (2013).

Kim, T.-G. et al. Dermal clusters of mature dendritic cells and T cells are associated with the CCL20/CCR6 chemokine system in chronic psoriasis. J. Invest. Dermatol. 134, 1462–1465 (2014).

Junt, T. et al. Subcapsular sinus macrophages in lymph nodes clear lymph-borne viruses and present them to antiviral B cells. Nature 450, 110–114 (2007).

Gerner, M. Y., Torabi-Parizi, P. & Germain, R. N. Strategically localized dendritic cells promote rapid T cell responses to lymph-borne particulate antigens. Immunity 42, 172–185 (2015).

Schumann, K. et al. Immobilized chemokine fields and soluble chemokine gradients cooperatively shape migration patterns of dendritic cells. Immunity 32, 703–713 (2010).

Del Prete, A. et al. Defective dendritic cell migration and activation of adaptive immunity in PI3Kγ-deficient mice. EMBO J. 23, 3505–3515 (2004).

van Rijn, A. et al. Semaphorin 7A promotes chemokine-driven dendritic cell migration. J. Immunol. 196, 459–468 (2016).

Myster, F. et al. Viral semaphorin inhibits dendritic cell phagocytosis and migration but is not essential for gammaherpesvirus-induced lymphoproliferation in malignant catarrhal fever. J. Virol. 89, 3630–3647 (2015).

Lämmermann, T. et al. Cdc42-dependent leading edge coordination is essential for interstitial dendritic cell migration. Blood 113, 5703–5710 (2009).

Harada, Y. et al. DOCK8 is a Cdc42 activator critical for interstitial dendritic cell migration during immune responses. Blood 119, 4451–4461 (2012).

Krishnaswamy, J. K. et al. Coincidental loss of DOCK8 function in NLRP10-deficient and C3H/HeJ mice results in defective dendritic cell migration. Proc. Natl Acad. Sci. USA 112, 3056–3061 (2015).

Gunawan, M. et al. The methyltransferase Ezh2 controls cell adhesion and migration through direct methylation of the extranuclear regulatory protein talin. Nat. Immunol. 16, 505–516 (2015).

Maddaluno, L. et al. The adhesion molecule L1 regulates transendothelial migration and trafficking of dendritic cells. J. Exp. Med. 206, 623–635 (2009).

Sozzani, S., Vermi, W., Del Prete, A. & Facchetti, F. Trafficking properties of plasmacytoid dendritic cells in health and disease. Trends Immunol. 31, 270–277 (2010).

Faure-André, G. et al. Regulation of dendritic cell migration by CD74, the MHC class II-associated invariant chain. Science 322, 1705–1710 (2008).

Frittoli, E. et al. The signaling adaptor Eps8 is an essential actin capping protein for dendritic cell migration. Immunity 35, 388–399 (2011).

Xu, Y. et al. Dendritic cell motility and T cell activation requires regulation of Rho-cofilin signaling by the Rho-GTPase activating protein myosin IXb. J. Immunol. 192, 3559–3568 (2014).

Lamsoul, I. et al. ASB2α regulates migration of immature dendritic cells. Blood 122, 533–541 (2013).

Ring, S. et al. Regulatory T cell-derived adenosine induces dendritic cell migration through the Epac–Rap1 pathway. J. Immunol. 194, 3735–3744 (2015).

Adkins, I. et al. Bordetella adenylate cyclase toxin differentially modulates Toll-like receptor-stimulated activation, migration and T cell stimulatory capacity of dendritic cells. PLoS ONE 9, e104064 (2014).

Solanes, P. et al. Space exploration by dendritic cells requires maintenance of myosin II activity by IP3 receptor 1. EMBO J. 34, 798–810 (2015).

Vargas, P. et al. Innate control of actin nucleation determines two distinct migration behaviours in dendritic cells. Nat. Cell Biol. 18, 43–53 (2016). This study identifies two main actin pools in DCs: one located in the rear drives forward locomotion, whereas the one in the front limits migration and directs antigen capture.

Thiam, H.-R. et al. Perinuclear Arp2/3-driven actin polymerization enables nuclear deformation to facilitate cell migration through complex environments. Nat. Commun. 7, 10997 (2016).

Gartlan, K. H. et al. Tetraspanin CD37 contributes to the initiation of cellular immunity by promoting dendritic cell migration. Eur. J. Immunol. 43, 1208–1219 (2013).

Jones, E. L. et al. Dendritic cell migration and antigen presentation are coordinated by the opposing functions of the tetraspanins CD82 and CD37. J. Immunol. 196, 978–987 (2016).

Srivatsan, S., Swiecki, M., Otero, K., Cella, M. & Shaw, A. S. CD2-associated protein regulates plasmacytoid dendritic cell migration, but is dispensable for their development and cytokine production. J. Immunol. 191, 5933–5940 (2013).

de Noronha, S. et al. Impaired dendritic-cell homing in vivo in the absence of Wiskott-Aldrich syndrome protein. Blood 105, 1590–1597 (2005).

Prete, F. et al. Wiskott-Aldrich syndrome protein-mediated actin dynamics control type-I interferon production in plasmacytoid dendritic cells. J. Exp. Med. 210, 355–374 (2013).

Worth, A. J. J. et al. Disease-associated missense mutations in the EVH1 domain disrupt intrinsic WASp function causing dysregulated actin dynamics and impaired dendritic cell migration. Blood 121, 72–84 (2013).

Cybulsky, M. I., Cheong, C. & Robbins, C. S. Macrophages and dendritic cells: partners in atherogenesis. Circ. Res. 118, 637–652 (2016).

Randolph, G. J. Mechanisms that regulate macrophage burden in atherosclerosis. Circ. Res. 114, 1757–1771 (2014).

Jongstra-Bilen, J. et al. Low-grade chronic inflammation in regions of the normal mouse arterial intima predisposed to atherosclerosis. J. Exp. Med. 203, 2073–2083 (2006).

Millonig, G. et al. Network of vascular-associated dendritic cells in intima of healthy young individuals. Arterioscler. Thromb. Vasc. Biol. 21, 503–508 (2001).

Choi, J.-H. et al. Identification of antigen-presenting dendritic cells in mouse aorta and cardiac valves. J. Exp. Med. 206, 497–505 (2009).

Paulson, K. E. et al. Resident intimal dendritic cells accumulate lipid and contribute to the initiation of atherosclerosis. Circ. Res. 106, 383–390 (2010).

Koltsova, E. K. et al. Dynamic T cell–APC interactions sustain chronic inflammation in atherosclerosis. J. Clin. Invest. 122, 3114–3126 (2012).

Weber, C. et al. CCL17-expressing dendritic cells drive atherosclerosis by restraining regulatory T cell homeostasis in mice. J. Clin. Invest. 121, 2898–2910 (2011).

Hu, D. et al. Artery tertiary lymphoid organs control aorta immunity and protect against atherosclerosis via vascular smooth muscle cell lymphotoxin β receptors. Immunity 42, 1100–1115 (2015).

Choi, J.-H. et al. Flt3 signaling-dependent dendritic cells protect against atherosclerosis. Immunity 35, 819–831 (2011).

Legein, B. et al. Ablation of CD8α + dendritic cell mediated cross-presentation does not impact atherosclerosis in hyperlipidemic mice. Sci. Rep. 5, 15414 (2015).

Zhang, Z. et al. Antigen-loaded dendritic cell migration: MR imaging in a pancreatic carcinoma model. Radiology 274, 192–200 (2015).

Kretzschmar, D. et al. Decrease in circulating dendritic cell precursors in patients with peripheral artery disease. Mediators Inflamm. 2015, 450957 (2015).

Van Vré, E. A. et al. Changes in blood dendritic cell counts in relation to type of coronary artery disease and brachial endothelial cell function. Coron. Artery Dis. 21, 87–96 (2010).

Angeli, V. et al. Dyslipidemia associated with atherosclerotic disease systemically alters dendritic cell mobilization. Immunity 21, 561–574 (2004).

Weitman, E. S. et al. Obesity impairs lymphatic fluid transport and dendritic cell migration to lymph nodes. PLoS ONE 8, e70703 (2013).

Nickel, T. et al. oxLDL downregulates the dendritic cell homing factors CCR7 and CCL21. Mediators Inflamm. 2012, 320953 (2012).

Luchtefeld, M. et al. Chemokine receptor 7 knockout attenuates atherosclerotic plaque development. Circulation 122, 1621–1628 (2010).

Feig, J. E. et al. Statins promote the regression of atherosclerosis via activation of the CCR7-dependent emigration pathway in macrophages. PLoS ONE 6, e28534 (2011).

Wan, W., Lionakis, M. S., Liu, Q., Roffê, E. & Murphy, P. M. Genetic deletion of chemokine receptor Ccr7 exacerbates atherogenesis in ApoE-deficient mice. Cardiovasc. Res. 97, 580–588 (2013).

Döring, Y. et al. Auto-antigenic protein-DNA complexes stimulate plasmacytoid dendritic cells to promote atherosclerosis. Circulation 125, 1673–1683 (2012).

Sage, A. P. et al. MHC class II-restricted antigen presentation by plasmacytoid dendritic cells drives proatherogenic T cell immunity. Circulation 130, 1363–1373 (2014).

Daissormont, I. T. et al. Plasmacytoid dendritic cells protect against atherosclerosis by tuning T-cell proliferation and activity. Circ. Res. 109, 1387–1395 (2011).

Randolph, G. J. Emigration of monocyte-derived cells to lymph nodes during resolution of inflammation and its failure in atherosclerosis. Curr. Opin. Lipidol. 19, 462–468 (2008).

Edelson, B. T. et al. Peripheral CD103 + dendritic cells form a unified subset developmentally related to CD8α + conventional dendritic cells. J. Exp. Med. 207, 823–836 (2010).

Cerovic, V. et al. Lymph-borne CD8α + dendritic cells are uniquely able to cross-prime CD8 + T cells with antigen acquired from intestinal epithelial cells. Mucosal Immunol. 8, 38–48 (2015).

Welty, N. E. et al. Intestinal lamina propria dendritic cells maintain T cell homeostasis but do not affect commensalism. J. Exp. Med. 210, 2011–2024 (2013).

Desch, A. N. et al. CD103 + pulmonary dendritic cells preferentially acquire and present apoptotic cell-associated antigen. J. Exp. Med. 208, 1789–1797 (2011).

Fossum, E. et al. Vaccine molecules targeting Xcr1 on cross-presenting DCs induce protective CD8 + T-cell responses against influenza virus. Eur. J. Immunol. 45, 624–635 (2015).

IIIb: Safety of mRNA vaccines

Much of the concern about mRNA vaccines has had to do with their novelty, but the reality is that this is a fairly extreme mischaracterization. The first instance of naked mRNA inducing an immune response was demonstrated in 1990 with mice and research into the concept has been ongoing since. Under ordinary circumstances it can take decades for a vaccine to make it from bench to bedside so it isn’t especially surprising that we do not have them in routine use yet. The major problem with nucleic acid vaccines in general has not been their safety, but their efficacy. It’s quite challenging to get any nucleic acid vaccine reliably in a cell and doing the things you want it to do, especially RNA. However, some studies have demonstrated very promising results. There has for instance been an mRNA vaccine tried that encoded rabies envelope glycoprotein which demonstrated protection against rabies in pigs upon challenge with the virus supplied directly to the brain and excellent antibody responses as well.

Another concern raised has been the idea that mRNA can somehow alter the host’s genome. That would actually be super cool and be huge for gene therapy (and I could finally give myself the giant bat wings I’ve always wanted) but this is not so. This is ordinarily impossible except if there is also a reverse transcriptase enzyme present that produces DNA from the RNA template, which is how retroviruses work. There is no such risk with any mRNA vaccine candidate. mRNA vaccines act entirely within the cytosol of the cell- they do not go near the nucleus where all the DNA is. That’s actually a major advantage of RNA-based vaccines over DNA ones.

How nucleic acids (DNA and RNA) can be distinguished as non-self or altered self to trigger immune responses. Broadly, a major factor is where the nucleic acid is located within the cell. DNA for example should not be found outside the nucleus or mitochondria of a cell. Another factor is the presence or absence of a cap on the mRNA (or whether it is the right cap), and whether or not the RNA is single stranded or not (all host RNA is single stranded viruses may have double stranded RNA genomes). Source.

An integrated look at mRNA vaccination via injection. The mRNA vaccines will be delivered inside lipid nanoparticles that enter the cells and be taken up by antigen presenting cells like dendritic cells. There the mRNA will induce production of the encoded antigen and its processing to activate the antigen-presenting cells. The antigen-presenting cells will go on to activate T cells, especially T follicular helper cells, inside the nearest lymph node to induce a T cell response. B cells will be activated by the T follicular helper cells to make antibodies. Figure 3 from

Another concern I’ve heard raised is the possibility of long-term consequences that do not present until years after vaccination. This is the ever-present specter that the anti-vaccine movement likes to toss out with every vaccine and is honestly a mythical entity. While vaccines can vanishingly rarely produce conditions that become chronic (e.g. Guillain-Barre syndrome), these manifest soon after vaccination. As I’ve discussed before, Shoenfeld’s syndrome has no good evidence to support it. mRNA inside the cell is extremely short-lived. A great deal of work has been done to come up with new ways in mRNA pharmacology to make it last longer without having to give another dose and much progress has been made in that regard but nonetheless, mRNA is an incredibly unstable molecule. In fact it can degrade itself if exposed to even a little bit of heat or base and for that reason has to be stored at- 80 °C (which is why no mRNA vaccine candidate is likely going to be the fix for COVID-19 in lower and middle income nations).

Some individuals have also zeroed in on the importance of interferon responses in the action of mRNA vaccines and raised questions about autoimmunity. The fact of the matter is that interferons represent an extremely effective and ubiquitous mechanism to deal with viral infection and while aberrant interferon signaling does play a role in some autoimmune diseases one has to hold this in context: virtually every viral infection you encounter is going to elicit the production of interferons. This is how we evolved to deal with viruses. If somehow you find yourself in the position that you are on the brink of autoimmune disease and all that’s needed is some interferon to kick that into gear (and we have no way of knowing who such individuals are) then the reality is avoiding an mRNA vaccine is going to do essentially nothing to modify your risk of developing that autoimmune disease. You are bound to develop an infection at some point which will produce those interferons.

With COVID-19 specifically, there has been concern raised based on previous vaccines against coronaviruses for Th2(/Th17)-mediated immunopathology due to a vaccine. This is definitely a valid safety concern. The absolute worst thing that could happen from a vaccine is that it not only fails to prevent the disease but actually causes more severe disease upon encounter with the pathogen. But here there is excellent news: mRNA vaccines produce a highly-Th1 polarized immune response with minimal Th2 or Th17 activation. Thus given what we know about COVID-19 and vaccines against its related predecessors, it is quite rational to pursue an mRNA vaccine-based platform.

CD40/CD40L Signaling Pathway

Cluster of differentiation 40, CD40 (also known TNFRSF5, Tumor necrosis factor receptor superfamily member 5.) is a costimulatory protein and expresses on antigen presenting cells (APC). In human, CD40 is coded by TNFRSF5 gene and has 7 transcripts. Its ligand, CD154 (CD40L), is a protein that is primarily expressed on activated T cells and is also a member of the TNF superfamily of molecules. From previous studies, we can know that the CD40-CD40L pathway has been found to be essential in mediating a broad variety of immune and inflammatory responses including T cell-dependent immunoglobulin class switching, memory B cell development, and germinal center formation. The TNFR-receptor associated factor adaptor proteins TRAF1, TRAF2, TRAF6 and possibly TRAF5 interacting with CD40 serve as mediators of the signal transduction. AT-hook transcription factor AKNA is reported to coordinately regulate the expression of CD40 and its ligand, which may be important for homotypic cell interactions. Besides, the interaction of CD40 and its ligand is found to be necessary for amyloid-beta-induced microglial activation, and thus is thought to be an early event in Alzheimer disease pathogenesis.

The function of pathway

Targeting the CD40L and CD40 pathway is a powerful means of attenuating autoreactive and alloreactive immune responses. The previous results show that the CD40L and CD40 pathway contributes to an enhancement of cellular immune responses by virtue of an interaction between CD40L expressed on activated antigen-specific CD4+ T cells and CD40 expressed on dendritic cells (DC). CD40 signaling into dendritic cells thereby transmits a signal to activate the APC, which results in upregulation of CD80, CD86, and other co-stimulatory molecules for the optimal stimulation of CD8+ antigen-specific T cell responses. In addition, CD40 also expresses in the macrophage and B cells. In macrophage, the primary signal for activation is IFN-γ from Th1 type CD4+T cells. The secondary signal is CD40L on the T cell which binds CD40 on the macrophage cell surface. As a result, the macrophage expresses more CD40 and TNF receptors on its surface which helps increase the level of activation. Increased activity results in the induction of potent microbicidal substances in the macrophage, including reactive oxygen species and nitric oxide, leading to the destruction of ingested microbe. B cells can also present antigens to helper T cells. If activated T cells recognize the peptide presented by the B cell, the CD40L on the T cell binds to the B cell's CD40 receptor, causing B cell activation. And then, the T cell also produces IL-2, which directly influences B cells. As a result of this net stimulation, the B cell can undergo division, antibody isotype switching, and differentiation to plasma cells. The end-result is a B cell that is able to mass-produce specific antibodies against an antigenic target. Besides, CD40 widely expresses on normal cells and tumor cells, including non-Hodgkin's and Hodgkin's lymphomas, myeloma and some carcinomas including nasopharynx, bladder, cervix, kidney and ovary. CD40 is also expressed on B cell precursors in the bone marrow, and there is some evidence that CD40-CD154 interactions may play a role in the control of B cell haematopoiesis.

Clinical significance

Because interaction of CD154 and CD40 has a key role in initiating alloimmune response and graft survival, subsequent to CD28, CD154-CD40 interactions are perhaps the most well-studied pathway in transplantation. Inhibition of CD154-CD40 interactions diminishes innate immune responses to transplanted tissue, resulting in diminished expansion and differentiation of allospecific CD4+ and CD8+ effector T cells. In addition to this potent effect on effector T cell responses, CD154 antagonism promotes conversion of conventional CD4+ T cells into Foxp3+ peripheral Treg cells and increases accumulation of Treg cells within the allograft and subsequently in the graft-draining LN. Evidence also exists to suggest that antagonism of CD154-CD40 interactions results in the upregulation of coinhibitory molecules on donor-reactive T cell populations, such as PD-1, KLRG-1, and TIM-3. CD154-CD40 interactions are also critical for the development of donor-specific antibody and antibody-mediated rejection, and therapeutic blockade of this pathway diminishes the development of alloreactive B cell germinal center responses in mice and mitigates antibody-mediated rejection of kidney allografts in non-human primates. Further, blockade of the CD154-CD40 pathway is perhaps the most potent method of long-term tolerance induction yet identified in experimental models of transplantation, in that recipient exposure to resting hematopoietic donor cells in the presence of CD154-CD40 blocking reagents has been shown to result in durable tolerance to skin, heart, and islet transplantation. It is interesting to note that this CD8+ T cell-intrinsic role for CD40-mediated costimulation was found not to play a role in the generation of pathogenelicited CD8+ T cell responses, highlighting a potential difference in the costimulatory requirements during alloimmune responses versus protective immunity. A potential explanation for this difference is the fact that ligation of Toll-like receptors (TLRs) expressed on CD8+ T cells in the setting of pathogen infection could compensate for the requirement for T cell-intrinsic CD40 signals. In addition, CD154 has proven to be expressed on CD11c+ DC following TLR ligation. Thus, while this pathway is likely to play during pathogen infection, the role of DC-derived CD154 in the execution of alloreactive immune responses remains to be determined. Lastly, the discovery that CD154 likely has another binding partner—CD11b (Mac-1) —sheds significant light on the mechanism by which CD154 blockade potently inhibits aspects of innate cell recruitment during transplantation. While the contribution of CD154-CD11b interactions to the development of alloimmunity remains an unexplored area, the potential role of this interaction will likely enter into the calculus of whether CD154 or CD40-directed reagents are likely to provide more favorable results for immune modulation in the setting of transplantation. Given the numerous and potent effects of therapeutic targeting of CD154-CD40 interactions in the setting of alloimmunity, interest in development of pharmacologic inhibitors for translation into clinical transplantation remains high. While early clinical trials were stymied by thromboembolic complications associated with the use of anti-CD154 reagents owing to the expression of CD154 on platelets, recent technological developments have resulted in the generation of potentially clinically translatable reagents for targeting this pathway. First, non-agonistic anti-CD40 antibodies are being developed in order to avoid the use of anti-CD154-associated coagulopathic events. With the increasing of understanding of CD154-CD40 pathway, a phase IIa clinical trial of an anti-CD40 mAb (ASKP1240) is currently underway for use in kidney transplantation, and therapeutic manipulation of the CD154-CD40 pathway in order to improve outcomes in transplantation might eventually become a clinical reality. The results of this trial will be very informative in evaluating the potential of harnessing this pathway to improve clinical outcomes in transplantation, and potentially autoimmunity.

The CD40/CD40L system is implicated in proinflammatory pathways and is expressed in a variety of cells such as immunity cells, the vascular wall and platelets. This means that this pathway may relate to tumor production. In clinical studies, patients with different cancers exhibit higher circulating sCD40L (the soluble form of CD40 ligand) levels, so sCD40L may serve as a useful biomarker of tumor. However, it remains unclear whether sCD40L can be used as a therapeutic target in carcinogenesis, as circulating sCD40L levels may only represent platelet activation. Therefore, there are a lot of clinical trials to elucidate the potential use of sCD40L as a reliable biomarker and therapeutic target in cancer treatment.

Immunology & Cell Biology

The May-June 2021 issue contains a Special Feature to celebrate the 100 years since the discovery of insulin. The discovery and, more recently, large-scale manufacture of insulin has transformed type 1 diabetes (T1D) from a uniformly fatal disease to a chronic one. The reviews in this Special Feature all orbit around insulin and T1D. Each review addresses a different outstanding scientific challenge posed by T1D. Collectively, these reviews underscore the far-reaching impact of the discovery of insulin – a great example of the power of basic science. They highlight both the tremendous advances that have been made and delineate the scientific and medical challenges that remain before T1D is curable, not just treatable. Immunology & Cell Biology thanks the coordinator of this Special Feature – Stuart Mannering – for his planning and input.

Image: A section from the pancreas of an organ donor who suffered from type 1 diabetes. The staining shows the insulin, contained within the beta cells. Small lymphoid cells that have infiltrated the islet can be seen, indicating that the insulin-producing beta cells within this islet are undergoing autoimmune destruction, leading to type 1 diabetes. (Image courtesy of Helen Thomas, Tom Loudovaris and Tom Kay and the Tom Mandel Islet Transplantation program and St Vincent’s Institute of Medical Research.)

The February 2021 issue of Immunology & Cell Biology contains a Special Feature on Omics in Immunology. Omics is a term that generally refers to the application of genomics technologies to molecular and cell biology, to investigate DNA, RNA, proteins and epigenetics landscapes. The power of these high-throughput technologies permits the generation of large data sets and these, combined with novel bioinformatics analyses, have increasingly been utilsied in biology, and particularly in immunology. Omics and bioinformatics have also had an impact on the research questions one can ask, and the training of new generation of scientists. For instance, recent advances in single cell genomics have finally allowed the investigation of heterogenous cell populations and detection of new cell types. In this Special Feature, a series of reviews explores recent advances in the application of omics and bioinformatics in immunology and microbiology. These articles exemplify the vast research work that has occurred in the last two decades on the application of omics in medical and basic science research, with the objective to provide the reader with an introductory view of the current state-of-the-art. Immunology & Cell Biology thanks the coordinators of this Special Feature – Fabio Luciani and Sam Hudson – for their planning and input.

The December 2020 issue contains a Special Feature on Infection and Immunity, featuring selected presentations from the 10 th Lorne Infection and Immunity Conference. This multidisciplinary conference aims to provide a forum for outstanding topical science, foster collaborations and opportunities for development to students, post-doctoral fellows and up-and-coming researchers, and to be a platform for immunologists and microbiologists to discuss host-pathogen interactions, innate immunity and adaptive immunity and microbiology relevant to infectious and inflammatory diseases. The breadth and excellence of science presented at this meeting is encompassed by the articles in this issue by Lamiable et al., Saunders et al. and Chua et al. Immunology & Cell Biology sincerely thanks the coordinators of this Special Feature – Jim Harris and Justine Mintern – for their planning and input.

Image Credit: owned by Visit Victoria Creator, Robert Blackburn.

Image: Appropriate B cell activation leads to a protective antibody response. However, inappropriate B cell activation can lead to failure of antibody production and infectious susceptibility on one hand, or autoantibody production on the other.

The April 2020 issue of Immunology & Cell Biology contains a Special Feature on Multifaceted roles of antibody Fc effector functions. Traditionally, antibody research has focused upon the recognition of antigens, in order to inhibit pathogens or block receptors. However, in recent years, there has been a growing appreciation for the critical value of the Fc region of antibodies. Despite the Fc region being designated as “constant,” it is a surprisingly mutable region, regulated by genetics and post‐translational modifications, which can result in structural changes that determine Fc functional capacity. This collection of Review articles covers the multifaceted functions of Fc antibodies for the control and protection against a range of infectious diseases including viral, parasitic and bacterial pathogens and examines the complexity behind the modulation of Fc effector functions in order to improve antibody-based vaccination or to enhance monoclonal antibody therapeutic interventions. However, these articles also emphasize the need for balanced antibody responses, caution against the pathogenic consequences of dysregulated Fc effector functions, while also highlighting the many unknowns and exciting avenues of research that are yet to be explored. Immunology & Cell Biology thanks the coordinator of this Special Feature – Amy Chung – for her planning and input.

Image: A graphical representation of the FcγR effector functions. From Chenoweth et al. Harnessing the immune system via FcγR function in immune therapy: a pathway to next-gen mAbs. Immunol Cell Biol 2020 98: 287-304 doi: 10.1111/imcb.12326

The August 2019 issue of Immunology & Cell Biology contains a Special Feature on Immunological Memory. The term “Immunological Memory” refers to the phenomenon that, after an initial exposure, immune mechanisms respond more vigorously to subsequent exposure to a pathogen. This is fundamental to the concept of immunity it is a cornerstone many immune-based therapies and it has been documented in human history for thousands of years. However, there remains much to be learned about the basic biology underlying this phenomenon. This series of articles explores recent advances in immunological memory, by examining our current understanding of CD4 T cell memory differentiation pathways, evaluating the impact of the microbiome on developing B and T cell memory and exploring the role of metabolism in control of memory cell development. The articles also highlight how our understanding of the basic biology of immunological memory can be used to refine the design of immunotherapies, including vaccines and cell-based cancer therapies. Finally, several articles explore the broadening definition of immunological memory, with an exploration of trained immunity and virtual memory cells. Immunology & Cell Biology thanks the coordinators of this Special Feature – Joanna Kirman, Kylie Quinn and Robert Seder – for their planning and input.

Image: A schematic representation of immunological memory—the magnitude of primary and secondary immune responses alongside pathogen load—as well as the contribution of the microbiome and metabolic pathways, trained and virtual memory mechanisms and the impact on design of immunotherapeutics, such as vaccines and CAR T cell therapy. Image courtesy of Kylie Quinn (RMIT University, Melbourne, Australia).

The April 2019 issue contains a Special Feature on Primary Immunodeficiencies. Inborn errors of immunity, or primary immunodeficiency disorders (PID), are monogenic diseases of the immune system. These affections give rise to complex diseases with a wide range of susceptibility to infections. The advent of next-generation sequencing has ushered in a Golden Age of PID research. The number of genes identified as responsible for PID has been rapidly rising, with a new PID gene identified on average every week for the past 10 years. Despite the recent explosion of knowledge, 90% of the estimated 3000 PID genes have yet to be studied. This Special Feature discusses recent advances in PID research, and what it means for our understanding of human immunology. Immunology & Cell Biology thanks the coordinators of this Special Feature – Adrian Liston & Stephanie Humblet-Baron – for their planning and input.

Image: Mechanistic dissection of the disruption caused to an immunological network, as identified by single cell sequencing. The pictured PID is driven by mutation in NFIL3 and results in excessive IL-1β production. Image courtesy of Adrian Liston (The Babraham Institute, Cambridge, UK) & Stephanie Humblet-Baron (KV Leuven, Belgium).

The March 2019 issue of Immunology & Cell Biology contains a Special Feature on Macrophages in tissue repair. In the late 18th century, Metchnikoff proposed the ‘phagocytosis theory’ in which he controversially placed the contribution of macrophages to organismal biology as being of even greater importance than their role in bactericidal defence. His view still prevails today, with macrophages appreciated as playing a fundamental role in the process of tissue repair. The present series of articles explores recent advances in this area, highlighting the importance of macrophage heterogeneity, plasticity, tissue specificity, activation status and cellular metabolism on the outcome of tissue repair. Finally, in a broader view of the repair process, the role of neutrophils as well as eicosanoids as supporting macrophage migration and polarisation is discussed. Immunology & Cell Biology thanks the coordinators of this Special Feature – Tiffany Bouchery and Nicola Harris – for their planning and input.

Image: Alveolar macrophages in a chronic obstructive pulmonary disease (COPD) patient precision-cut lung slice stained for epithelial cells (epithelial cell adhesion molecule EpCAM in green) and macrophages (CD206 in purple). Image courtesy of Franz Puttur, Inflammation, Repair & Development, National Heart & Lung Institute, Imperial College London, UK.

The August 2018 issue contains a Special Feature on Extracellular Vesicles and Immune Modulation. There is a variety of extracellular vesicles (EV) produced by cells, including but not limited to exosomes, microvesicles and apoptotic vesicles. Once thought of as a way to jettison cellular waste, it has become apparent that EV are an integral compartment of a cell, albeit one that can act at a distance to transmit intercellular messages. This series of articles looks particularly at how blood and immune cell function are regulated by EV. From extracellular antigen presentation, through to the modulation of immune activity by pathogens, parasites and pregnancy, cancer cell immune evasion, and the effect of chemotherapy on blood cell function, EV play a critical role in cell communication. Immunology & Cell Biology thanks the coordinator of this Special Feature – Melanie McConnell – for her planning and input.

Image: Flow cytometric analysis of extracellular vesicles in conditioned media from cell lines indicates the presence of a diverse population of vesicles less than 1 micron in diameter. A vesicle in the same conditioned media was imaged by transmission electron microscopy. Image courtesy of Matthew Rowe and Melanie McConnell, Victoria University of Wellington.

The July 2018 issue contains a Special Feature on MAIT cells. Mucosal Associated Invariant T (MAIT) cells are an innate-like T-cell population that have attracted increasing amounts of attention, especially in the last few years since their specificity has been defined. In humans, these cells are very abundant, notably in organs such as the liver, but also in blood, so they are readily identified and studied, and we have also learned a lot from animal models. In this series of reviews, we discuss the development of MAIT cells and the fine details of their T-cell receptor recognition of MR-1 and the ligands it binds. We also discuss the functions of these cells in a variety of settings, taking into account the emerging data on their diverse triggering mechanisms. This field is developing rapidly and we hope to capture these new advances and the questions they pose in this set of reviews. Immunology & Cell Biology thanks the coordinators of this Special Feature – Daniel Pellicci and Paul Klenerman – for their planning and input.

Image: The MHC-like molecule MR1 captures vitamin B derivatives from microbes and presents them to MAIT cells. Depicted is a model of MR1-5-OP-RU from the crystal structure that also includes a MAIT TCR (PDB ID: 4QNC) overlayed with a picture of the yellow crystal of the same complex. Credit (used with permission): Michael Kai (, Stéphane Marchaud & Sidonia Eckle

The May/June 2018 issue contains a Special Feature on Immune homeostasis in health and disease. This series explores the mechanisms that maintain homeostasis across a variety of key immune cell lineages. Important themes include how these mechanisms adjust with challenges as diverse as infection, cancer or drug exposure to maintain homeostasis, or the adaption to chronic conditions that impose new set-points to limit tissue damage. This Special Feature also explores the prospects for translating these mechanistic insights in each of the main immune lineages into new targets for immune disorders. Immunology & Cell Biology thanks the coordinators of this Special Feature – Daniel Gray and Nick Huntington – for their planning and input.

Image: EM image of an NK cell harassing a cancer cell for consideration. Credit (used with permission): Fernando Guimaraes (The Walter and Eliza Hall Institute of Medical Research, Australia) and Carolina Oliveira (Universidade Federal do Paraná, Brazil)

The July 2017 issue contains a Special Feature on Advanced microscopy and imaging techniques in Immunology and Cell Biology. Since microscopes were first invented, scientists have constantly been drawn to these marvellous machines. This is because microscopes provide their user with the ability to view first hand minuscule objects and processes they have often dedicated their entire careers to studying. It is this ability to view biology at work in both space and time, from a single molecule to an entire organism that makes imaging such a powerful tool. In this Special Feature, we have compiled a series of articles that discuss the history of microscopes and imaging modalities. We look at how current platforms have influenced basic research of immunology and cell biology as well as their use in the clinic to diagnose and treat disease. We also discuss how future developments in technology will open avenues for an even deeper understanding of fundamental principles in biology and the challenges associated with handling vast amounts of data generated by technology that gives such a high level of detailed information. Immunology & Cell Biology thanks the coordinator of this Special Feature – Edwin Hawkins – for his planning and input.

The April 2017 issue of Immunology & Cell Biology contains a Special Feature on Cancer Immunotherapy. This series of reviews highlights some of the recent advances in mobilizing effective host immunity to cancer. Cancer immunotherapy is at a critical and exciting stage of development. Progress in our understanding of cancer immunotherapy has been dramatic over recent years and we have selected six articles to highlight in this Special Feature. The Special Feature begins with an overview of the approaches to targeting inflammation in the cancer microenvironment and follows with a focus of extracellular adenosine as a major immunosuppressive metabolite in tumours. Two subsequent articles detail advances in antibody engineering for engaging the ideal effector responses in tumours and the Special Feature finishes with two articles that explore new approaches in adoptive cellular therapy targeted at tumor and virus specific antigens in tumors. Immunology & Cell Biology thanks the coordinator of this Special Feature – Mark Smyth – for his planning and input.

The February 2017 issue contains a Special Feature on Necroptotic death signalling: evolution, mechanisms and disease relevance. In recent years, research into a genetically encoded cell death program termed necroptosis has accelerated into vogue. Many laboratories are now racing to answer key questions such as: How does it occur? When does it occur? What does it do? What is it good (or not so good) for? Answers to these will ultimately guide efforts aimed at manipulating this new pathway for therapeutic benefit. In the six articles in this ICB Special Feature, the current state of play in necroptotic cell death research is dissected in considerable detail. The articles provide timely updates on what we have learnt so far and, importantly, where we might be going. Immunology & Cell Biology thanks the coordinator of this Special Feature – James Vince – for his planning and input.

The November/December 2016 issue contains a Special Feature on Novel aspects of autoimmunity. Major scientific advances often arise at the interface of disciplines, or are made possible by transformative technological advances. Progress in our understanding of the basis of autoimmunity over recent years provides great examples of this, and we have selected four of these to highlight in this ICB Special Feature. Together these articles reveal how recent technological advances have revealed important mechanisms underlying autoimmune disease, mechanisms that can now be examined in humans as well as mouse models. Our increasing ability to conduct in-depth studies in humans promises to continue to unlock the mysteries underlying autoimmunity, with inevitable benefits to patients with these diseases. Immunology & Cell Biology thanks the coordinators of this Special Feature – Ken Smith and Arthur Kaser – for their planning and input.

The March 2016 issue contains a Special Feature on Cutting-edge single-cell genomics and modelling in immunology. The recent advent of single-cell genomics has offered unprecedented possibilities for hypothesis-independent characterization of cellular heterogeneity and regulatory states. At the same time, the vast datasets produced by these techniques have highlighted the need for new bioinformatics tools to utilize the contained information to the fullest. In this Special Feature, both the experimental methods for producing such data as well as selected modelling approaches are reviewed, with focus on the applications on the study of the immune system. Immunology and Cell Biology thanks the coordinators of this Special Feature – Tapio Lönnberg and Valentina Proserpio – for their planning and input.

The February 2016 issue contains a Special Feature on the Effects of exercise on the immune system and metabolism coming into the Olympic year. The role of the immune system in exercise is complex and challenging. Too little exercise can depress the immune system. In contrast, too much exercise can also lead to a compromised immune system. This is a challenge that athletes face as they prepare for competition. Immunology & Cell Biology thanks the coordinators of this Special Feature – Mark Febbraio and Graeme Lancaster – for their planning and input.

The last two years has seen substantial progress in identifying the molecules and mechanisms responsible for non-apoptotic programmed cell death, which are highlighted in this web focus. These include the pro-inflammatory lytic cell death pathways mediated by either caspase-1 or caspase-11, termed pyroptosis, or RIPK3 and MLKL, referred to as necroptosis. Emerging evidence suggests significant cross-talk between different cell death modalities, including the negative regulation of necroptosis by key extrinsic apoptotic components, and the ability of the necroptotic machinery to activate inflammasome associated caspase-1. These selected papers cover the importance of these pathways to human health and disease, highlight discoveries in their mechanism of action and cross-talk, and document their regulation by pathogen derived molecules.

The launch of the European Congress of Immunology (6-9th September) in Vienna this year, together with the hosting of the inaugural joint workshop between the German and Australasian Societies for Immunology in Canberra, Australia (3-4th December) which will be followed by the International Congress in Immunology in Melbourne (21-26th August, 2016) highlights the strong links forged between the Asia Pacific and Europe. This served as a great opportunity to highlight key studies published over the last two years in Immunology and Cell Biology highlighting the work of our European collaborators.

The January 2015 issue contains a Special Feature on Autophagy and Immunity. Autophagy is an essential process to maintain cellular homeostasis and functions. It is responsible for the lysosome-mediated degradation of damaged proteins and organelles, and dysregulation of this pathway contributes to the development of a variety of diseases in man including diabetes, neurodegeneration and cancer. Recent studies have illuminated the importance of the regulatory pathways that control autophagy and the wide range of physiological processes it regulates in humans. Immunology & Cell Biology thanks the coordinators of this Special Feature — Jim Harris and Justine Mintern — for their planning and input.

Immunology & Cell Biology celebrates 90 years of publication in the current year. The journal was founded in 1924 and a testament to the importance of this journal is that it has become home to a number of landmark papers in the field. This includes many primary works by Macfarlane Burnet, winner of the Nobel Prize for Medicine and Physiology (1960) for and Donald Metcalf, winner of the Lasker

DeBakey Clinical Medical Research Award (1993).

Metabolism and pathogen defense are essential requirements for survival. Mounting an immune response requires major changes to metabolic processes, and immune mediators (such as cytokines) also dictate changes in metabolism, including endocrine regulation of substrate utilization. The April 2014 issue contains a Special Feature on Immunometabolism: The interface of immune and metabolic responses in disease.

Histone deacetylases (HDAC) and inhibitors have already been shown to be beneficial for use as mood stabilizers, anti-epileptics and also in the treatment of certain cancers. The January 2012 issue will include a review series on histone deacetylases (HDAC) and inhibitors in immunology, focusing on the mechanisms that contribute to therapeutic effects of HDAC inhibitors in immune-related diseases and determining the relevant HDACs in different immune-related diseases.

Our understanding of the significance and complexity of the chemokine superfamily has increased at an explosive pace over the last decade. Although this pace may be slowing down, many questions remain in this field. The February 2011 Special Feature on Chemokines reviews some of these issues: the CXCR3/CXCL9/CXCL10/CXCL11 axis the role of chemokines in the thymus and the function of the atypical chemokine receptors DARC and D6, the two best characterised members of this fledgling chemokine receptor subfamily. A selection of recent articles provides further insight into our current understanding of this complex superfamily.

Fifty years ago Macfarlane Burnet and Peter Medawar won the Nobel Prize in Physiology or Medicine for their discovery of acquired immunological tolerance. Their discovery has since inspired a whole series of experiments that have uncovered many of the core principles of immunology. The January 2011 Special Feature on Immunological Tolerance presents eight reviews on various aspects of immunological tolerance, including T cell-MHC interactions, the complex molecular controls dictating cell death or survival, apoptosis, the role of the thymus in immunity, regulatory T cells, the peripheral stages of immunological tolerance, and autoimmunity. The accompanying web focus expands on the topic, providing a selection of related articles and reviews that have been published over the past two years.

Understanding Th2 differentiation of activated naïve CD4 T cells continues to be a topic of intense investigation. The March/April 2010 Special Feature on What Drives Th2 Immunity looks at the factors involved in Th2 differentiation, the cellular sources of Th2-inducing factors and the induction of Th2 immunity in vivo, and provides a summary of Th2 differentiation and immunity in vitro and in vivo. The accompanying web focus presents a collection of articles that further outline our current understanding.

Spanning the breadth of immunology, Immunology & Cell Biology is proud to present Featured Outstanding Observations and Theoretical Articles - a collection of some of the top articles from recent years. Outstanding Observations describe striking, reproducible observations that have extremely important conceptual implications but do not necessarily include insights into the underlying molecular mechanisms. Theoretical Articles are intended to challenge and provoke discussion in the international scientific community.

Vaccines are one of the most effective methods of controlling infectious disease. Although vaccination has been used for centuries, the technologies are largely empirical with little understanding of the underlying immunological principles and physiological mechanisms. As researchers gain knowledge of these principles and regulatory authorities become more stringent in their requirements, changes in empirical approaches have become necessary rational vaccine design is now essential. The articles in this special feature introduce research on a new generation of vaccines which are logically designed and evaluated. Of particular interest is a new wave of vaccines that induce CD8+ T cell responses — in contrast to the traditional mechanism of eliciting a protective antibody response — and how they may be used therapeutically. The accompanying web focus delves deeper into vaccine research, placing recent discoveries into context.

The two greatest challenges facing the widespread use of transplanted organs are availability of suitable organs and prevention of graft rejection by the host's immune system. This special feature on transplantation immunobiology addresses the two approaches to overcome these problems: obtaining transplantable organs from animals (usually pigs) rather than humans (known as xenotransplantation), and developing clever ways of specifically suppressing the recipient's immune system (regulatory T cells are proving relevant) rather than using current, non-specific immunosuppressive drugs that have considerable side effects. The accompanying web focus delves into the various techniques currently available for preventing xenotransplant rejection by modifying the graft, and explores approaches aimed at developing immunological tolerance to transplanted tissues in graft recipients.

Initially, it was thought that primary lymphoid organs exclusively produce cells and that once cells left, few would re-enter. However, recent data have shown that numerous cell types can return to the thymus. This focus brings together a collection of articles representing our current understanding of the field. The accompanying special feature deals with the nature and possible functional consequences of cellular traffic, both lymphoid and myeloid, back to the primary lymphoid organs.

Carbohydrates are involved in a range of interactions related to immune responses. This collection of recent review and research articles represents our current understanding of the roles glycans play in activating the adaptive and innate immune responses.

Spanning the breadth of immunology, Immunology & Cell Biology is proud to present a selection of the top articles from 2007 and 2008. With a particular emphasis on the cell biology of the immune system, areas covered include: cellular immunology, innate and adaptive immunity, immune responses to pathogens, tumour immunology, immunopathology, immunotherapy, immunogenetics and immunological studies in humans and model organisms (including mouse, rat, Drosophila etc).

This focus presents a collection of review and research articles that outline our current understanding of DC heterogeneity, how different populations contribute to T cell responses, and how T cells differentiate and maintain functional diversity. As well as highlighting the recent advances, the accompanying two-part special feature also identifies the gaps in our understanding and the potential this holds for the future.

The incredible impact on international science of a small paper published 50 years ago is worth celebrating as an exemplar of the immense power of one idea to change our world.

A collection of the best articles from the long and illustrious history of Immunology & Cell Biology: the favourite icon of immunology, Sir Frank Macfarlane Burnet.

ELife digest

Cells generally communicate with each other over short distances by direct contact, and over long distances by releasing chemicals such as hormones. But there is also a third way that is less well understood – small capsules or “vesicles” called exosomes can transfer molecules from one cell to another. Exosomes are involved in the immune response and have been linked to a number of diseases, including cancer and neurodegeneration. However, scientists are still trying to understand how exosomes are made, what they contain and how they are released from cells.

A common set of cells used in laboratory studies are known as HeLa cells. These cells are the descendants of cancerous cells taken from a patient called Henrietta Lacks in 1951. When treated with a particular drug, HeLa cells produce vesicles that look like exosomes. Yet instead of moving freely like other exosomes, these structures stick together in clusters. This raises questions – are these cancer cell vesicles truly exosomes? And if so, why and how are they tethered to the cell?

Using electron microscopy and biochemical tests, Edgar et al. confirm that the unusual vesicles produced by HeLa cells are exosomes. As well as sharing characteristics with other exosomes, the vesicles also show similarities with viruses like HIV, which attach themselves to cell surfaces and each other using a protein called tetherin. Using a technique called gene editing to remove tetherin from HeLa cells allowed the exosomes in the cluster to move apart.

Further investigation revealed that some cells in the immune system also produce exosome clusters and that these clusters also contain tetherin. Edgar et al. propose that cells control whether exosomes are involved in short-range or long-range communication by controlling the amount of tetherin they produce.

So far, studies into the roles that exosomes play in the body have been hampered by a lack of experimental tools. The study by Edgar et al. opens up new methods of investigation by providing ways of altering the number of exosomes released from a cell. This should help to clarify what exosomes do and how they work in a wide range of different cell types.


any member of a unique class of infectious agents, which were originally distinguished by their smallness (hence, they were described as &ldquofiltrable&rdquo because of their ability to pass through fine ceramic filters that blocked all cells, including bacteria) and their inability to replicate outside of and without assistance of a living host cell. Because these properties are shared by certain bacteria ( rickettsiae, chlamydiae ), viruses are now characterized by their simple organization and their unique mode of replication. A virus consists of genetic material, which may be either DNA or RNA, and is surrounded by a protein coat and, in some viruses, by a membranous envelope.

Unlike cellular organisms, viruses do not contain all the biochemical mechanisms for their own replication they replicate by using the biochemical mechanisms of a host cell to synthesize and assemble their separate components. (Some do contain or produce essential enzymes when there is no cellular enzyme that will serve.) When a complete virus particle ( virion ) comes in contact with a host cell, only the viral nucleic acid and, in some viruses, a few enzymes are injected into the host cell.

Within the host cell the genetic material of a DNA virus is replicated and transcribed into messenger RNA by host cell enzymes, and proteins coded for by viral genes are synthesized by host cell ribosomes. These are the proteins that form the capsid (protein coat) there may also be a few enzymes or regulatory proteins involved in assembling the capsid around newly synthesized viral nucleic acid, in controlling the biochemical mechanisms of the host cell, and in lysing the host cell when new virions have been assembled. Some of these may already have been present within the initial virus, and others may be coded for by the viral genome for production within the host cell.

Because host cells do not have the ability to replicate &ldquoviral RNA&rdquo but are able to transcribe messenger RNA, RNA viruses must contain enzymes to produce genetic material for new virions. For certain viruses the RNA is replicated by a viral enzyme ( transcriptase ) contained in the virion, or produced by the host cell using the viral RNA as a messenger. In other viruses a reverse transcriptase contained in the virion transcribes the genetic message on the viral RNA into DNA, which is then replicated by the host cell. Reverse transcriptase is actually a combination of two enzymes: a polymerase that assembles the new DNA copy and an RNase that degrades the source RNA.

In viruses that have membranes, membrane-bound viral proteins are synthesized by the host cell and move, like host cell membrane proteins, to the cell surface. When these proteins assemble to form the capsid, part of the host cell membrane is pinched off to form the envelope of the virion.

Some viruses have only a few genes coding for capsid proteins. Other more complex ones may have a few hundred genes. But no virus has the thousands of genes required by even the simplest cells. Although in general viruses &ldquosteal&rdquo their lipid envelope from the host cell, virtually all of them produce &ldquoenvelope proteins&rdquo that penetrate the envelope and serve as receptors. Some envelope proteins facilitate viral entry into the cell, and others have directly pathogenic effects.

Some viruses do not produce rapid lysis of host cells, but rather remain latent for long periods in the host before the appearance of clinical symptoms. This carrier state can take any of several different forms. The term latency is used to denote the interval from infection to clinical manifestations. In the lentiviruses , it was formerly mistakenly believed that virus was inactive during this period. The true situation is that lentiviruses are rapidly replicating and spawning dozens of quasi-species until a particularly effective one overruns the ability of the host's immune system to defeat it. Other viruses, however, such as the herpesviruses , actually enter a time known as &ldquoviral latency,&rdquo when little or no replication is taking place until further replication is initiated by a specific trigger. For many years all forms of latency were thought to be identical, but now it has been discovered that there are different types with basic and important distinctions.

In viral latency, most of the host cells may be protected from infection by immune mechanisms involving antibodies to the viral particles or interferon . Cell-mediated immunity is essential, especially in dealing with infected host cells. Cytotoxic lymphocytes may also act as antigen-presenting cells to better coordinate the immune response . Containment of virus in mucosal tissues is far more complex, involving follicular dendritic cells and Langerhans cells .

Some enveloped RNA viruses can be produced in infected cells that continue growing and dividing without being killed. This probably involves some sort of intracellular regulation of viral growth. It is also possible for the DNA of some viruses to be incorporated into the host cell DNA, producing a carrier state. These are almost always retroviruses , which are called proviruses before and after integration of viral DNA into the host genome.

Few viruses produce toxins, although viral infections of bacteria can cause previously innocuous bacteria to become much more pathogenic and toxic. Other viral proteins, such as some of the human immunodeficiency virus , appear to be actively toxic, but those are the exception, not the rule.

However, viruses are highly antigenic. Mechanisms of pathologic injury to cells include cell lysis induction of cell proliferation (as in certain warts and molluscum contagiosum ) formation of giant cells, syncytia, or intracellular inclusion bodies caused by the virus and perhaps most importantly, symptoms caused by the host's immune response , such as inflammation or the deposition of antigen-antibody complexes in tissues.

Because viral reproduction is almost completely carried out by host cell mechanisms, there are few points in the process where stopping viral reproduction will not also kill host cells. For this reason there are no chemotherapeutic agents for most viral diseases. acyclovir is an antiviral that requires viral proteins to become active. Some viral infections can be prevented by vaccination (active immunization ), and others can be treated by passive immunization with immune globulin , although this has been shown to be effective against only a few dozen viruses.

Watch the video: Antigen Presenting Cells APC (June 2022).


  1. Radbert

    I hate to read

  2. Aubry

    not logically

  3. Ferenc

    I am sorry, that has interfered... I understand this question. Write here or in PM.

Write a message