Key Points
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Expression levels of the activating Fc receptors for IgG (FcγRs) are much higher on monocyte-derived dendritic cells (moDCs) and macrophages than on conventional DCs (cDCs) and plasmacytoid DCs (pDCs), and can be used to separate these cells in mice and humans. The inhibitory FcγR is broadly expressed on all antigen-presenting cells (APCs).
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The uptake of antigens via distinct extracellular and intracellular FcγRs influences antigen presentation, and determines whether the antigen is degraded or presented and the type of epitopes that are presented.
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Most FcγRs induce the expression of activating signals in APCs that can influence APC activation, the ability of APCs to kill pathogens and the APC-mediated regulation of T cell responses. Through concomitant expression of the inhibitory FcγR, the immune system can set strict activation thresholds in particular APCs.
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The main function of activating FcγRs on moDCs is to modify the encounters of moDCs with T cells at sites of inflammation, whereas the function of FcγRs on macrophages is to promote the clearance of pathogens in the periphery.
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The role of FcγRs on cDCs and pDCs deserves more attention as there is a striking lack of studies that address the role of FcγRs on these cells in vivo. The main function of the inhibitory FcγR on these cells might be the induction of tolerance.
Abstract
Dendritic cells (DCs) and macrophages use various receptors to recognize foreign antigens and to receive feedback control from adaptive immune cells. Although it was long believed that all immunoglobulin Fc receptors are universally expressed by phagocytes, recent findings indicate that only monocyte-derived DCs and macrophages express high levels of activating Fc receptors for IgG (FcγRs), whereas conventional and plasmacytoid DCs express the inhibitory FcγR. In this Review, we discuss how the uptake, processing and presentation of antigens by DCs and macrophages is influenced by FcγR recognition of immunoglobulins and immune complexes in the steady state and during inflammation.
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Change history
07 April 2014
In the version of this Review that was initially published, the images in Table 2 showing the structure of FcγRIIB and FcγRIII were in the wrong order. This error has been corrected in the online HTML and PDF versions of the article. Nature Reviews Immunology apologizes for this error.
References
Jönsson, F. & Daëron, M. Mast cells and company. Front. Immunol. 3, 16 (2012).
Nimmerjahn, F. & Ravetch, J. V. Fcγ receptors as regulators of immune responses. Nature Rev. Immunol. 8, 34–47 (2008).
Roopenian, D. C. & Akilesh, S. FcRn: the neonatal Fc receptor comes of age. Nature Rev. Immunol. 7, 715–725 (2007).
James, L. C., Keeble, A. H., Khan, Z., Rhodes, D. A. & Trowsdale, J. Structural basis for PRYSPRY-mediated tripartite motif (TRIM) protein function. Proc. Natl Acad. Sci. USA 104, 6200–6205 (2007).
Mallery, D. L. et al. Antibodies mediate intracellular immunity through tripartite motif-containing 21 (TRIM21). Proc. Natl Acad. Sci. USA 107, 19985–19990 (2010).
Daëron, M. Fc receptor biology. Annu. Rev. Immunol. 15, 203–234 (1997).
Blank, U., Launay, P., Benhamou, M. & Monteiro, R. C. Inhibitory ITAMs as novel regulators of immunity. Immunol. Rev. 232, 59–71 (2009).
Amigorena, S. et al. Cytoplasmic domain heterogeneity and functions of IgG Fc receptors in B lymphocytes. Science 256, 1808–1812 (1992).
Ono, M., Bolland, S., Tempst, P. & Ravetch, J. V. Role of the inositol phosphatase SHIP in negative regulation of the immune system by the receptor FcγRIIB. Nature 383, 263–266 (1996).
Daëron, M., Jaeger, S., Du Pasquier, L. & Vivier, E. Immunoreceptor tyrosine-based inhibition motifs: a quest in the past and future. Immunol. Rev. 224, 11–43 (2008).
Smith, K. G. & Clatworthy, M. R. FcγRIIB in autoimmunity and infection: evolutionary and therapeutic implications. Nature Rev. Immunol. 10, 328–343 (2010). This paper is a particularly comprehensive review of the biology and functions of FcγRIIB.
Bruhns, P. Properties of mouse and human IgG receptors and their contribution to disease models. Blood 119, 5640–5649 (2012). A review that is focused on human and mouse FcγRs, highlighting their differences and the roles that have been attributed to them as a result of transgenic mouse models.
Nimmerjahn, F. & Ravetch, J. V. Fcγ receptors: old friends and new family members. Immunity 24, 19–28 (2006).
Mancardi, D. A. et al. The high-affinity human IgG receptor FcγRI (CD64) promotes IgG-mediated inflammation, anaphylaxis, and antitumor immunotherapy. Blood 121, 1563–1573 (2013).
Mancardi, D. A. et al. FcγRIV is a mouse IgE receptor that resembles macrophage FcεRI in humans and promotes IgE-induced lung inflammation. J. Clin. Invest. 118, 3738–3750 (2008).
Mancardi, D. A. et al. The murine high-affinity IgG receptor FcγRIV is sufficient for autoantibody-induced arthritis. J. Immunol. 186, 1899–1903 (2011).
van der Poel, C. E., Spaapen, R. M., van de Winkel, J. G. & Leusen, J. H. Functional characteristics of the high affinity IgG receptor, FcγRI. J. Immunol. 186, 2699–2704 (2011).
Li, X., Ptacek, T. S., Brown, E. E. & Edberg, J. C. Fcγ receptors: structure, function and role as genetic risk factors in SLE. Genes Immun. 10, 380–389 (2009).
Nimmerjahn, F. & Ravetch, J. V. Translating basic mechanisms of IgG effector activity into next generation cancer therapies. Cancer Immun. 12, 13 (2012).
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).
Schlitzer, A. et al. IRF4 transcription factor-dependent CD11b+ dendritic cells in human and mouse control mucosal IL-17 cytokine responses. Immunity 38, 970–983 (2013).
Gatto, D. et al. The chemotactic receptor EBI2 regulates the homeostasis, localization and immunological function of splenic dendritic cells. Nature Immunol. 14, 446–453 (2013).
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).
Karsten, C. M. & Kohl, J. The immunoglobulin, IgG Fc receptor and complement triangle in autoimmune diseases. Immunobiology 217, 1067–1079 (2012).
Gautier, E. L. et al. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nature Immunol. 13, 1118–1128 (2012). This article from the Immunological Genome Consortium identifies FcγRI and the tyrosine protein kinase MER (MERTK) as markers that discriminate between mouse cDCs and moDCs or macrophages.
Miller, J. C. et al. Deciphering the transcriptional network of the dendritic cell lineage. Nature Immunol. 13, 888–899 (2012).
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).
Flinsenberg, T. W. et al. Fcγ receptor antigen targeting potentiates cross-presentation by human blood and lymphoid tissue BDCA-3+ dendritic cells. Blood 120, 5163–5172 (2012). This article provides flow cytometry data showing FcγR expression by distinct human immune cell populations.
Robbins, S. H. et al. Novel insights into the relationships between dendritic cell subsets in human and mouse revealed by genome-wide expression profiling. Genome Biol. 9, R17 (2008).
Haniffa, M. et al. Human tissues contain CD141hi cross-presenting dendritic cells with functional homology to mouse CD103+ nonlymphoid dendritic cells. Immunity 37, 60–73 (2012).
Segura, E. et al. Characterization of resident and migratory dendritic cells in human lymph nodes. J. Exp. Med. 209, 653–660 (2012).
Biburger, M. et al. Monocyte subsets responsible for immunoglobulin G-dependent effector functions in vivo. Immunity 35, 932–944 (2011).
Dobel, T. et al. FcγRIII (CD16) equips immature 6-sulfo LacNAc-expressing dendritic cells (slanDCs) with a unique capacity to handle IgG-complexed antigens. Blood 121, 3609–3618 (2013).
Flores, M. et al. Dominant expression of the inhibitory FcγRIIB prevents antigen presentation by murine plasmacytoid dendritic cells. J. Immunol. 183, 7129–7139 (2009). This article provides flow cytometry data showing FcγR expression by distinct mouse immune cell populations.
Seeling, M. et al. Inflammatory monocytes and Fcγ receptor IV on osteoclasts are critical for bone destruction during inflammatory arthritis in mice. Proc. Natl Acad. Sci. USA 110, 10729–10734 (2013).
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).
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). References 23, 27, 36 and 37 show the use of FcγRI as a marker to discriminate between mouse cDCs and moDCs and macrophages.
Guriec, N., Daniel, C., Le Ster, K., Hardy, E. & Berthou, C. Cytokine-regulated expression and inhibitory function of FcγRIIB1 and -B2 receptors in human dendritic cells. J. Leukoc. Biol. 79, 59–70 (2006).
Liu, S. et al. HMGB1 is secreted by immunostimulated enterocytes and contributes to cytomix-induced hyperpermeability of Caco-2 monolayers. Am. J. Physiol. Cell Physiol. 290, C990–C999 (2006).
Nimmerjahn, F., Bruhns, P., Horiuchi, K. & Ravetch, J. V. FcγRIV: a novel FcR with distinct IgG subclass specificity. Immunity 23, 41–51 (2005).
te Velde, A. A., de Waal Malefijt, R., Huijbens, R. J., de Vries, J. E. & Figdor, C. G. IL-10 stimulates monocyte FcγR surface expression and cytotoxic activity. Distinct regulation of antibody-dependent cellular cytotoxicity by IFNγ, IL-4, and IL-10. J. Immunol. 149, 4048–4052 (1992).
Boruchov, A. M. et al. Activating and inhibitory IgG Fc receptors on human DCs mediate opposing functions. J. Clin. Invest. 115, 2914–2923 (2005).
Segura, E. et al. Human inflammatory dendritic cells induce TH17 cell differentiation. Immunity 38, 336–348 (2013). This article shows the use of FcεRI as a marker to discriminate between human cDCs and moDCs.
Means, T. K. et al. Human lupus autoantibody–DNA complexes activate DCs through cooperation of CD32 and TLR9. J. Clin. Invest. 115, 407–417 (2005).
Amigorena, S., Salamero, J., Davoust, J., Fridman, W. H. & Bonnerot, C. Tyrosine-containing motif that transduces cell activation signals also determines internalization and antigen presentation via type III receptors for IgG. Nature 358, 337–341 (1992).
Miettinen, H. M., Rose, J. K. & Mellman, I. Fc receptor isoforms exhibit distinct abilities for coated pit localization as a result of cytoplasmic domain heterogeneity. Cell 58, 317–327 (1989).
Amigorena, S. & Bonnerot, C. Fc receptor signaling and trafficking: a connection for antigen processing. Immunol. Rev. 172, 279–284 (1999).
Bergtold, A., Desai, D. D., Gavhane, A. & Clynes, R. Cell surface recycling of internalized antigen permits dendritic cell priming of B cells. Immunity 23, 503–514 (2005).
Hoffmann, E. et al. Autonomous phagosomal degradation and antigen presentation in dendritic cells. Proc. Natl Acad. Sci. USA 109, 14556–14561 (2012). This report shows that IgG-mediated opsonization enhances antigen presentation to CD4+ T cells only when antigens and IgG are present within the same phagosome.
Qiao, S. W. et al. Dependence of antibody-mediated presentation of antigen on FcRn. Proc. Natl Acad. Sci. USA 105, 9337–9342 (2008).
Baker, K. et al. Neonatal Fc receptor for IgG (FcRn) regulates cross-presentation of IgG immune complexes by CD8-CD11b+ dendritic cells. Proc. Natl Acad. Sci. USA 108, 9927–9932 (2011). References 50 and 51 show the role of FcRn in antigen presentation by DCs when antigens are opsonized by IgG.
Zhu, X. et al. MHC class I-related neonatal Fc receptor for IgG is functionally expressed in monocytes, intestinal macrophages, and dendritic cells. J. Immunol. 166, 3266–3276 (2001).
Vidarsson, G. et al. FcRn: an IgG receptor on phagocytes with a novel role in phagocytosis. Blood 108, 3573–3579 (2006).
McEwan, W. A. et al. Intracellular antibody-bound pathogens stimulate immune signaling via the Fc receptor TRIM21. Nature Immunol. 14, 327–336 (2013). References 5 and 54 describe TRIM21 as an intracellular IgG receptor.
McEwan, W. A., Mallery, D. L., Rhodes, D. A., Trowsdale, J. & James, L. C. Intracellular antibody-mediated immunity and the role of TRIM21. Bioessays 33, 803–809 (2011).
Bonnerot, C. et al. Syk protein tyrosine kinase regulates Fc receptor γ-chain-mediated transport to lysosomes. EMBO J. 17, 4606–4616 (1998).
Odin, J. A., Edberg, J. C., Painter, C. J., Kimberly, R. P. & Unkeless, J. C. Regulation of phagocytosis and [Ca2+]i flux by distinct regions of an Fc receptor. Science 254, 1785–1788 (1991).
Edberg, J. C. et al. The cytoplasmic domain of human FcγRIa alters the functional properties of the FcγRI γ-chain receptor complex. J. Biol. Chem. 274, 30328–30333 (1999).
Li, F. & Ravetch, J. V. A general requirement for FcγRIIB co-engagement of agonistic anti-TNFR antibodies. Cell Cycle 11, 3343–3344 (2012).
Hernandez, M., Fuentes, L., Fernandez Aviles, F. J., Crespo, M. S. & Nieto, M. L. Secretory phospholipase A2 elicits proinflammatory changes and upregulates the surface expression of fas ligand in monocytic cells: potential relevance for atherogenesis. Circul. Res. 90, 38–45 (2002).
Dhodapkar, K. M. et al. Selective blockade of the inhibitory Fcγ receptor (FcγRIIB) in human dendritic cells and monocytes induces a type I interferon response program. J. Exp. Med. 204, 1359–1369 (2007).
Sutterwala, F. S., Noel, G. J., Clynes, R. & Mosser, D. M. Selective suppression of interleukin-12 induction after macrophage receptor ligation. J. Exp. Med. 185, 1977–1985 (1997). This article describes the alternative activation state of macrophages following FcγR triggering.
Mosser, D. M. & Edwards, J. P. Exploring the full spectrum of macrophage activation. Nature Rev. Immunol. 8, 958–969 (2008).
Mantovani, A. et al. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 25, 677–686 (2004).
Clynes, R. et al. Modulation of immune complex-induced inflammation in vivo by the coordinate expression of activation and inhibitory Fc receptors. J. Exp. Med. 189, 179–185 (1999).
Yuasa, T. et al. Deletion of fcγ receptor IIB renders H-2b mice susceptible to collagen-induced arthritis. J. Exp. Med. 189, 187–194 (1999).
Clatworthy, M. R. & Smith, K. G. FcγRIIb balances efficient pathogen clearance and the cytokine-mediated consequences of sepsis. J. Exp. Med. 199, 717–723 (2004).
Brownlie, R. J. et al. Distinct cell-specific control of autoimmunity and infection by FcγRIIb. J. Exp. Med. 205, 883–895 (2008). References 65–68 show that the balance between activating ITAM-bearing FcγRs and the inhibitory ITIM-bearing FcγRIIB controls the threshold for cell activation.
Hubber, A. & Roy, C. R. Modulation of host cell function by Legionella pneumophila type IV effectors. Annu. Rev. Cell Dev. Biol. 26, 261–283 (2010).
Hunter, C. A. & Sibley, L. D. Modulation of innate immunity by Toxoplasma gondii virulence effectors. Nature Rev. Microbiol. 10, 766–778 (2012).
Joller, N. et al. Antibodies protect against intracellular bacteria by Fc receptor-mediated lysosomal targeting. Proc. Natl Acad. Sci. USA 107, 20441–20446 (2010).
Maglione, P. J., Xu, J., Casadevall, A. & Chan, J. Fcγ receptors regulate immune activation and susceptibility during Mycobacterium tuberculosis infection. J. Immunol. 180, 3329–3338 (2008).
Joller, N., Weber, S. S. & Oxenius, A. Antibody-Fc receptor interactions in protection against intracellular pathogens. Eur. J. Immunol. 41, 889–897 (2011).
Yona, S. et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38, 79–91 (2013).
Schulz, C. et al. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336, 86–90 (2012).
Hashimoto, D. et al. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 38, 792–804 (2013).
Guilliams, M. et al. Alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via GM-CSF. J. Exp. Med. 210, 1977–1992 (2013).
Halstead, S. B., Mahalingam, S., Marovich, M. A., Ubol, S. & Mosser, D. M. Intrinsic antibody-dependent enhancement of microbial infection in macrophages: disease regulation by immune complexes. Lancet Infect. Dis. 10, 712–722 (2010).
Guzman, M. G. & Vazquez, S. The complexity of antibody-dependent enhancement of dengue virus infection. Viruses 2, 2649–2662 (2010).
Kliks, S. C., Nimmanitya, S., Nisalak, A. & Burke, D. S. Evidence that maternal dengue antibodies are important in the development of dengue hemorrhagic fever in infants. Am. J. Trop. Med. Hyg. 38, 411–419 (1988).
Gonzalez, D. et al. Classical dengue hemorrhagic fever resulting from two dengue infections spaced 20 years or more apart: Havana, Dengue 3 epidemic, 2001–2002. Int. J. Infect. Dis. 9, 280–285 (2005).
Denkers, E. Y. & Butcher, B. A. Sabotage and exploitation in macrophages parasitized by intracellular protozoans. Trends Parasitol. 21, 35–41 (2005).
Yang, Z., Mosser, D. M. & Zhang, X. Activation of the MAPK, ERK, following Leishmania amazonensis infection of macrophages. J. Immunol. 178, 1077–1085 (2007).
Padigel, U. M. & Farrell, J. P. Control of infection with Leishmania major in susceptible BALB/c mice lacking the common γ-chain for FcR is associated with reduced production of IL-10 and TGF-β by parasitized cells. J. Immunol. 174, 6340–6345 (2005).
Kima, P. E. et al. Internalization of Leishmania mexicana complex amastigotes via the Fc receptor is required to sustain infection in murine cutaneous leishmaniasis. J. Exp. Med. 191, 1063–1068 (2000).
Miles, S. A., Conrad, S. M., Alves, R. G., Jeronimo, S. M. & Mosser, D. M. A role for IgG immune complexes during infection with the intracellular pathogen Leishmania. J. Exp. Med. 201, 747–754 (2005).
Regnault, A. et al. Fcγ receptor-mediated induction of dendritic cell maturation and major histocompatibility complex class I-restricted antigen presentation after immune complex internalization. J. Exp. Med. 189, 371–380 (1999).
Heijnen, I. A. et al. Antigen targeting to myeloid-specific human FcγRI/CD64 triggers enhanced antibody responses in transgenic mice. J. Clin. Invest. 97, 331–338 (1996). References 45, 87 and 88 show that FcγR triggering improves presentation of an antigen that is contained in an immune complex.
den Haan, J. M. & Bevan, M. J. Constitutive versus activation-dependent cross-presentation of immune complexes by CD8+ and CD8− dendritic cells in vivo. J. Exp. Med. 196, 817–827 (2002).
Tobar, J. A., Gonzalez, P. A. & Kalergis, A. M. Salmonella escape from antigen presentation can be overcome by targeting bacteria to Fcγ receptors on dendritic cells. J. Immunol. 173, 4058–4065 (2004).
Akiyama, K. et al. Targeting apoptotic tumor cells to FcγR provides efficient and versatile vaccination against tumors by dendritic cells. J. Immunol. 170, 1641–1648 (2003).
Celis, E. & Chang, T. W. Antibodies to hepatitis B surface antigen potentiate the response of human T lymphocyte clones to the same antigen. Science 224, 297–299 (1984).
van Montfoort, N. et al. Fcγ receptor IIb strongly regulates Fcγ receptor-facilitated T cell activation by dendritic cells. J. Immunol. 189, 92–101 (2012).
Schuurhuis, D. H. et al. Antigen-antibody immune complexes empower dendritic cells to efficiently prime specific CD8+ CTL responses in vivo. J. Immunol. 168, 2240–2246 (2002).
Rafiq, K., Bergtold, A. & Clynes, R. Immune complex-mediated antigen presentation induces tumor immunity. J. Clin. Invest. 110, 71–79 (2002).
Desai, D. D. et al. Fcγ receptor IIB on dendritic cells enforces peripheral tolerance by inhibiting effector T cell responses. J. Immunol. 178, 6217–6226 (2007).
Yada, A. et al. Accelerated antigen presentation and elicitation of humoral response in vivo by FcγRIIB- and FcγRI/III-mediated immune complex uptake. Cell. Immunol. 225, 21–32 (2003). References 89, 93 and 97 show that antigens associated with immunoglobulins are more efficiently cross-presented by DCs.
de Jong, J. M. et al. Murine Fc receptors for IgG are redundant in facilitating presentation of immune complex derived antigen to CD8+ T cells in vivo. Mol. Immunol. 43, 2045–2050 (2006).
Ioan-Facsinay, A. et al. FcγRI (CD64) contributes substantially to severity of arthritis, hypersensitivity responses, and protection from bacterial infection. Immunity 16, 391–402 (2002). Together with reference 14, this paper demonstrates the contribution of FcγRI to IgG-mediated immune response in vivo.
Dhodapkar, K. M. et al. Selective blockade of inhibitory Fcγ receptor enables human dendritic cell maturation with IL-12p70 production and immunity to antibody-coated tumor cells. Proc. Natl Acad. Sci. USA 102, 2910–2915 (2005).
Liu, Y. et al. Regulated expression of FcγR in human dendritic cells controls cross-presentation of antigen-antibody complexes. J. Immunol. 177, 8440–8447 (2006).
Dai, X. et al. Differential signal transduction, membrane trafficking, and immune effector functions mediated by FcγRI versus FcγRIIa. Blood 114, 318–327 (2009). This study shows that even if two different FcγRs are associated with the same signalling subunit (that is, the FcR γ-chain), their downstream signalling is dissimilar and leads to different cellular responses.
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).
McLachlan, J. B., Catron, D. M., Moon, J. J. & Jenkins, M. K. Dendritic cell antigen presentation drives simultaneous cytokine production by effector and regulatory T cells in inflamed skin. Immunity 30, 277–288 (2009).
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).
Woelbing, F. et al. Uptake of Leishmania major by dendritic cells is mediated by Fcγ receptors and facilitates acquisition of protective immunity. J. Exp. Med. 203, 177–188 (2006).
Bjorck, P., Beilhack, A., Herman, E. I., Negrin, R. S. & Engleman, E. G. Plasmacytoid dendritic cells take up opsonized antigen leading to CD4+ and CD8+ T cell activation in vivo. J. Immunol. 181, 3811–3817 (2008).
Bandukwala, H. S. et al. Signaling through FcγRIII is required for optimal T helper type (TH)2 responses and TH2-mediated airway inflammation. J. Exp. Med. 204, 1875–1889 (2007).
Kitamura, K. et al. Critical role of the Fc receptor γ-chain on APCs in the development of allergen-induced airway hyperresponsiveness and inflammation. J. Immunol. 178, 480–488 (2007). References 61, 93, 95, 106, 108 and 109 collectively show that FcγR triggering induces DC maturation and increases their capacity to induce the differentiation of effector T cells (that is, T H 1 or T H 2 cells, depending on the model).
Hartwig, C. et al. Fcγ receptor-mediated antigen uptake by lung DC contributes to allergic airway hyper-responsiveness and inflammation. Eur. J. Immunol. 40, 1284–1295 (2010).
Tjota, M. Y. et al. IL-33-dependent induction of allergic lung inflammation by FcγRIII signaling. J. Clin. Invest. 123, 2287–2297 (2013).
Blink, S. E. & Fu, Y. X. IgE regulates T helper cell differentiation through FcγRIII mediated dendritic cell cytokine modulation. Cell. Immunol. 264, 54–60 (2010).
Kalergis, A. M. & Ravetch, J. V. Inducing tumor immunity through the selective engagement of activating Fcγ receptors on dendritic cells. J. Exp. Med. 195, 1653–1659 (2002).
McGaha, T. L., Karlsson, M. C. & Ravetch, J. V. FcγRIIB deficiency leads to autoimmunity and a defective response to apoptosis in Mrl-MpJ mice. J. Immunol. 180, 5670–5679 (2008).
Samsom, J. N. et al. FcγRIIB regulates nasal and oral tolerance: a role for dendritic cells. J. Immunol. 174, 5279–5287 (2005).
Wenink, M. H. et al. The inhibitory FcγIIb receptor dampens TLR4-mediated immune responses and is selectively up-regulated on dendritic cells from rheumatoid arthritis patients with quiescent disease. J. Immunol. 183, 4509–4520 (2009).
Laborde, E. A. et al. Immune complexes inhibit differentiation, maturation, and function of human monocyte-derived dendritic cells. J. Immunol. 179, 673–681 (2007).
Tridandapani, S. et al. Regulated expression and inhibitory function of FcγRIIb in human monocytic cells. J. Biol. Chem. 277, 5082–5089 (2002).
Tridandapani, S. et al. TGF-β1 suppresses [correction of supresses] myeloid Fcγ receptor function by regulating the expression and function of the common γ-subunit. J. Immunol. 170, 4572–4577 (2003).
Pricop, L. et al. Differential modulation of stimulatory and inhibitory Fcγ receptors on human monocytes by TH1 and TH2 cytokines. J. Immunol. 166, 531–537 (2001).
Sallusto, F. & Lanzavecchia, A. Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin-4 and downregulated by tumor necrosis factor-α. J. Exp. Med. 179, 1109–1118 (1994).
Tel, J. et al. Human plasmacytoid dendritic cells efficiently cross-present exogenous Ags to CD8+ T cells despite lower Ag uptake than myeloid dendritic cell subsets. Blood 121, 459–467 (2013).
Benitez-Ribas, D. et al. Plasmacytoid dendritic cells of melanoma patients present exogenous proteins to CD4+ T cells after FcγRII-mediated uptake. J. Exp. Med. 203, 1629–1635 (2006).
Benitez-Ribas, D., Tacken, P., Punt, C. J., de Vries, I. J. & Figdor, C. G. Activation of human plasmacytoid dendritic cells by TLR9 impairs FcγRII-mediated uptake of immune complexes and presentation by MHC class II. J. Immunol. 181, 5219–5224 (2008).
Kool, M. et al. Facilitated antigen uptake and timed exposure to TLR ligands dictate the antigen-presenting potential of plasmacytoid DCs. J. Leukoc. Biol. 90, 1177–1190 (2011). References 123, 124 and 125 show that triggering of FcγRs endows pDCs with the capacity to efficiently present antigens to T cells.
Gilliet, M., Cao, W. & Liu, Y. J. Plasmacytoid dendritic cells: sensing nucleic acids in viral infection and autoimmune diseases. Nature Rev. Immunol. 8, 594–606 (2008).
Tian, J. et al. Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nature Immunol. 8, 487–496 (2007).
Henault, J. et al. Noncanonical autophagy is required for type I interferon secretion in response to DNA-immune complexes. Immunity 37, 986–997 (2012). DNA-containing immune complexes induce type I IFN secretion by pDCs through a convergence of the phagocytic and the non-canonical autophagic pathway.
Parcina, M. et al. Staphylococcus aureus-induced plasmacytoid dendritic cell activation is based on an IgG-mediated memory response. J. Immunol. 181, 3823–3833 (2008).
Tel, J. et al. Targeted delivery of CpG ODN to CD32 on human and monkey plasmacytoid dendritic cells augments IFNα secretion. Immunobiology 217, 1017–1024 (2012).
Boule, M. W. et al. Toll-like receptor 9-dependent and -independent dendritic cell activation by chromatin-immunoglobulin G complexes. J. Exp. Med. 199, 1631–1640 (2004).
Clynes, R. A., Towers, T. L., Presta, L. G. & Ravetch, J. V. Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nature Med. 6, 443–446 (2000).
Schwab, I. & Nimmerjahn, F. Intravenous immunoglobulin therapy: how does IgG modulate the immune system? Nature Rev. Immunol. 13, 176–189 (2013).
Kaneko, Y., Nimmerjahn, F., Madaio, M. P. & Ravetch, J. V. Pathology and protection in nephrotoxic nephritis is determined by selective engagement of specific Fc receptors. J. Exp. Med. 203, 789–797 (2006).
Samuelsson, A., Towers, T. L. & Ravetch, J. V. Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor. Science 291, 484–486 (2001).
Crow, A. R. et al. IVIg-mediated amelioration of murine ITP via FcγRIIB is independent of SHIP1, SHP-1, and Btk activity. Blood 102, 558–560 (2003).
Bruhns, P., Samuelsson, A., Pollard, J. W. & Ravetch, J. V. Colony-stimulating factor-1-dependent macrophages are responsible for IVIG protection in antibody-induced autoimmune disease. Immunity 18, 573–581 (2003).
Siragam, V. et al. Intravenous immunoglobulin ameliorates ITP via activating Fcγ receptors on dendritic cells. Nature Med. 12, 688–692 (2006).
Bayry, J. et al. Inhibition of maturation and function of dendritic cells by intravenous immunoglobulin. Blood 101, 758–765 (2003).
Anthony, R. M., Kobayashi, T., Wermeling, F. & Ravetch, J. V. Intravenous gammaglobulin suppresses inflammation through a novel TH2 pathway. Nature 475, 110–113 (2011).
Akilesh, S. et al. The MHC class I-like Fc receptor promotes humorally mediated autoimmune disease. J. Clin. Invest. 113, 1328–1333 (2004).
Serbina, N. V. & Pamer, E. G. Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nature Immunol. 7, 311–317 (2006).
Grayson, M. H. et al. Induction of high-affinity IgE receptor on lung dendritic cells during viral infection leads to mucous cell metaplasia. J. Exp. Med. 204, 2759–2769 (2007).
Hammad, H. et al. Inflammatory dendritic cells — not basophils — are necessary and sufficient for induction of TH2 immunity to inhaled house dust mite allergen. J. Exp. Med. 207, 2097–2111 (2010). References 23, 143 and 144 show the power of using FcγRI and FcεRI as markers to discriminate between mouse cDCs and moDCs.
Painter, M. W., Davis, S., Hardy, R. R., Mathis, D. & Benoist, C. Transcriptomes of the B and T lineages compared by multiplatform microarray profiling. J. Immunol. 186, 3047–3057 (2011).
Stetson, D. B. & Medzhitov, R. Recognition of cytosolic DNA activates an IRF3-dependent innate immune response. Immunity 24, 93–103 (2006).
Zigmond, E. et al. Ly6Chi monocytes in the inflamed colon give rise to proinflammatory effector cells and migratory antigen-presenting cells. Immunity 37, 1076–1090 (2012).
Lee, S. M. et al. Systems-level comparison of host-responses elicited by avian H5N1 and seasonal H1N1 influenza viruses in primary human macrophages. PLoS ONE 4, e8072 (2009).
Braun, D. A., Fribourg, M. & Sealfon, S. C. Cytokine response is determined by duration of receptor and signal transducers and activators of transcription 3 (STAT3) activation. J. Biol. Chem. 288, 2986–2993 (2013).
Martinez, F. O. et al. Genetic programs expressed in resting and IL-4 alternatively activated mouse and human macrophages: similarities and differences. Blood 121, e57–e69 (2013).
Saylor, C. A., Dadachova, E. & Casadevall, A. Murine IgG1 and IgG3 isotype switch variants promote phagocytosis of Cryptococcus neoformans through different receptors. J. Immunol. 184, 336–343 (2010).
Steinman, R. M. & Cohn, Z. A. Identification of a novel cell type in peripheral organs in mice. II. Functional properties in vitro. 139, 380–397 (1974).
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Glossary
- Antibody-dependent cell-mediated cytotoxicity
-
(ADCC). A mechanism by which cytotoxic effector cells, including natural killer (NK) cells, kill other cells, for example, virus-infected target cells that are coated with antibodies. The Fc portions of the coating antibodies interact with the Fc receptor that is expressed by the cytotoxic effector cell, thereby initiating a signalling cascade that leads to cellular activation and target cell killing. The precise killing mechanism depends on the type of cytotoxic effector cell.
- Immune complexes
-
Complexes of antigens that are bound to antibodies and, sometimes, components of the complement system. The concentration of immune complexes is increased in many autoimmune disorders, in which the immune complexes become deposited in tissues and cause tissue damage.
- Mononuclear phagocyte system
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(MPS). Bone marrow-derived cells with different morphologies (that is, monocytes, macrophages and dendritic cells) that are mainly responsible for phagocytosis, cytokine secretion and antigen presentation.
- Neonatal FcR
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(FcRn). Unrelated to classical Fc receptors (FcRs) and binds to a different region in the antibody Fc fragment. It is structurally related to the family of MHC class I molecules and is responsible for regulating IgG half-life.
- Cross-presentation
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The initiation of a CD8+ T cell response to an antigen that is not present within antigen-presenting cells (APCs). This exogenous antigen must be taken up by APCs and then re-routed to the MHC class I pathway of antigen presentation.
- Monocyte-derived DCs
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(moDCs). In vitro-generated monocyte-derived DCs are the most studied DC subset and can be obtained in large quantities by culturing mouse bone marrow cells in granulocyte–macrophage colony-stimulating factor (GM-CSF), or by culturing human peripheral blood monocytes in GM-CSF and interleukin-4 (IL-4).
- Group 2 innate lymphoid cells
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These cells predominantly produce type 2 cytokines and require the transcription factors retinoic acid receptor-related orphan receptor-α (RORα) and GATA-binding protein 3 (GATA3) for their development and function.
- Intravenous immunoglobulin therapy
-
(IVIG therapy). Injection of high doses of polyclonal antibodies into patients.
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Guilliams, M., Bruhns, P., Saeys, Y. et al. The function of Fcγ receptors in dendritic cells and macrophages. Nat Rev Immunol 14, 94–108 (2014). https://doi.org/10.1038/nri3582
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DOI: https://doi.org/10.1038/nri3582
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