Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Fcγ receptors as regulators of immune responses

Key Points

  • The family of Fc receptors for IgG (FcγRs) is broadly expressed by cells of haematopoietic origin and consists of one inhibitory and several activating receptors that differ in their affinity and specificity for immunoglobulin subclasses.

  • On innate immune effector cells, activating and inhibitory FcγRs set a threshold for cell activation by immune complexes. Important examples for effector responses that are regulated by FcγRs are phagocytosis, ADCC and the release of inflammatory mediators.

  • On dendritic cells (DCs), paired FcγR expression regulates cell maturation and antigen presentation, thereby indirectly controlling the cellular immune response.

  • On B cells, the inhibitory FcγRIIB is essential for the maintenance of humoral tolerance. It acts as a late checkpoint at the level of class-switched memory B cells, plasmablasts or plasma cells. In addition, FcγRIIB has an important role in regulating plasma-cell homeostasis and survival.

  • The antibody–FcγR interaction is influenced by several factors that have an impact on the expression level of activating and inhibitory FcγRs (such as cytokines) or change the affinity of the antibody–FcγR interaction (such as differential antibody glycosylation).

  • Depending on the specific glycosylation pattern, IgG molecules can have enhanced pro- or anti-inflammatory activities. Importantly, antibody glycosylation is regulated during immune responses.

  • Targeting the factors that influence the antibody–FcγR interaction might open new avenues for immunotherapeutic interventions in autoimmune and malignant diseases.

Abstract

In addition to their role in binding antigen, antibodies can regulate immune responses through interacting with Fc receptors (FcRs). In recent years, significant progress has been made in understanding the mechanisms that regulate the activity of IgG antibodies in vivo. In this Review, we discuss recent studies addressing the multifaceted roles of FcRs for IgG (FcγRs) in the immune system and how this knowledge could be translated into novel therapeutic strategies to treat human autoimmune, infectious or malignant diseases.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Regulatory functions of immune complexes.
Figure 2: The family of Fc receptors for IgG.
Figure 3: Antibody–FcγR interactions.
Figure 4: Signalling pathways triggered by activating and inhibitory FcγRs.
Figure 5: FcγRIIB as a checkpoint of humoral tolerance.

Similar content being viewed by others

References

  1. Ravetch, J. V. & Lanier, L. L. Immune inhibitory receptors. Science 290, 84–89 (2000).

    Article  CAS  PubMed  Google Scholar 

  2. Nimmerjahn, F. Activating and inhibitory FcγRs in autoimmune disorders. Springer Semin. Immunopathol. 28, 305–319 (2006).

    Article  CAS  PubMed  Google Scholar 

  3. Bolland, S. & Ravetch, J. V. Inhibitory pathways triggered by ITIM-containing receptors. Adv. Immunol. 72, 149–177 (1999).

    Article  CAS  PubMed  Google Scholar 

  4. Nimmerjahn, F. & Ravetch, J. V. Fcγ receptors: old friends and new family members. Immunity 24, 19–28 (2006).

    CAS  PubMed  Google Scholar 

  5. Ravetch, J. V. in Fundamental Immunology (ed. Paul, W. E.) 685–700 (Lippincott-Raven, Philadelphia, 2003).

    Google Scholar 

  6. Dijstelbloem, H. M., van de Winkel, J. G. & Kallenberg, C. G. Inflammation in autoimmunity: receptors for IgG revisited. Trends Immunol. 22, 510–516 (2001).

    Article  CAS  PubMed  Google Scholar 

  7. Nimmerjahn, F., Bruhns, P., Horiuchi, K. & Ravetch, J. V. FcγRIV: a novel FcR with distinct IgG subclass specificity. Immunity 23, 41–51 (2005). This study identifies FcγRIV as a functional activating FcR that is responsible for mediating the activity of IgG2a and IgG2b antibody subclasses in vivo.

    Article  CAS  PubMed  Google Scholar 

  8. Anderson, C. L. & Grey, H. M. Receptors for aggregated IgG on mouse lymphocytes: their presence on thymocytes, thymus-derived, and bone marrow-derived lymphocytes. J. Exp. Med. 139, 1175–1188 (1974).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Leclerc, J. C., Plater, C. & Fridman, W. H. The role of the Fc receptor (FcR) of thymus-derived lymphocytes. I. Presence of FcR on cytotoxic lymphocytes and absence of direct role in cytotoxicity. Eur. J. Immunol. 7, 543–548 (1977).

    Article  CAS  PubMed  Google Scholar 

  10. Stout, R. D. & Herzenberg, L. A. The Fc receptor on thymus-derived lymphocytes. I. Detection of a subpopulation of murine T lymphocytes bearing the Fc receptor. J. Exp. Med. 142, 611–621 (1975).

    Article  CAS  PubMed  Google Scholar 

  11. Takai, T. Roles of Fc receptors in autoimmunity. Nature Rev. Immunol. 2, 580–592 (2002).

    Article  CAS  Google Scholar 

  12. Hulett, M. D. & Hogarth, P. M. Molecular basis of Fc receptor function. Adv. Immunol. 57, 1–127 (1994).

    Article  CAS  PubMed  Google Scholar 

  13. Galli, S. J. et al. Mast cells as “tunable” effector and immunoregulatory cells: recent advances. Annu. Rev. Immunol. 23, 749–786 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. Gould, H. J. et al. The biology of IgE and the basis of allergic disease. Annu. Rev. Immunol. 21, 579–628 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. Nimmerjahn, F. & Ravetch, J. V. Divergent immunoglobulin G subclass activity through selective Fc receptor binding. Science 310, 1510–1512 (2005).

    Article  CAS  PubMed  Google Scholar 

  16. Hamaguchi, Y., Xiu, Y., Komura, K., Nimmerjahn, F. & Tedder, T. F. Antibody isotype-specific engagement of Fcγ receptors regulates B lymphocyte depletion during CD20 immunotherapy. J. Exp. Med. 203, 743–753 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Garman, S. C., Kinet, J. P. & Jardetzky, T. S. Crystal structure of the human high-affinity IgE receptor. Cell 95, 951–961 (1998).

    Article  CAS  PubMed  Google Scholar 

  18. Maxwell, K. F. et al. Crystal structure of the human leukocyte Fc receptor, Fc γRIIa. Nature Struct. Biol. 6, 437–442 (1999).

    Article  CAS  PubMed  Google Scholar 

  19. Sondermann, P., Huber, R. & Jacob, U. Crystal structure of the soluble form of the human Fcγ-receptor IIb: a new member of the immunoglobulin superfamily at 1.7 Å resolution. EMBO J. 18, 1095–1103 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sondermann, P., Kaiser, J. & Jacob, U. Molecular basis for immune complex recognition: a comparison of Fc-receptor structures. J. Mol. Biol. 309, 737–749 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. Radaev, S. & Sun, P. Recognition of immunoglobulins by Fcγ receptors. Mol. Immunol. 38, 1073–1083 (2002).

    Article  CAS  PubMed  Google Scholar 

  22. Allen, J. M. & Seed, B. Isolation and expression of functional high-affinity Fc receptor complementary DNAs. Science 243, 378–381 (1989).

    Article  CAS  PubMed  Google Scholar 

  23. Corper, A. L. et al. Structure of human IgM rheumatoid factor Fab bound to its autoantigen IgG Fc reveals a novel topology of antibody-antigen interaction. Nature Struct. Biol. 4, 374–381 (1997).

    Article  CAS  PubMed  Google Scholar 

  24. Deisenhofer, J. Crystallographic refinement and atomic models of a human Fc fragment and its complex with fragment B of protein A from Staphylococcus aureus at 2.9- and 2.8-Å resolution. Biochemistry 20, 2361–2370 (1981).

    Article  CAS  PubMed  Google Scholar 

  25. DeLano, W. L., Ultsch, M. H., de Vos, A. M. & Wells, J. A. Convergent solutions to binding at a protein–protein interface. Science 287, 1279–1283 (2000).

    Article  CAS  PubMed  Google Scholar 

  26. Harris, L. J. et al. The three-dimensional structure of an intact monoclonal antibody for canine lymphoma. Nature 360, 369–372 (1992).

    Article  CAS  PubMed  Google Scholar 

  27. Martin, W. L., West, A. P., Jr., Gan, L. & Bjorkman, P. J. Crystal structure at 2.8 Å of an FcRn/heterodimeric Fc complex: mechanism of pH-dependent binding. Mol. Cell 7, 867–877 (2001).

    Article  CAS  PubMed  Google Scholar 

  28. Saphire, E. O. et al. Contrasting IgG structures reveal extreme asymmetry and flexibility. J. Mol. Biol. 319, 9–18 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Matsumiya, S. et al. Structural comparison of fucosylated and nonfucosylated Fc fragments of human immunoglobulin G1. J. Mol. Biol. 368, 767–779 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Radaev, S., Motyka, S., Fridman, W. H., Sautes-Fridman, C. & Sun, P. D. The structure of a human type III Fcγ receptor in complex with Fc. J. Biol. Chem. 276, 16469–16477 (2001).

    Article  CAS  PubMed  Google Scholar 

  31. Sondermann, P., Huber, R., Oosthuizen, V. & Jacob, U. The 3.2-Å crystal structure of the human IgG1 Fc fragment-FcγRIII complex. Nature 406, 267–273 (2000). By generating a crystal structure of human FcγRIIIA in complex with human IgG1, the authors of this study provide fascinating insights into the antibody-FcR interaction on an atomic level; see also reference 30.

    Article  CAS  PubMed  Google Scholar 

  32. Kato, K., Fridman, W. H., Arata, Y. & Sautes-Fridman, C. A conformational change in the Fc precludes the binding of two Fcγ receptor molecules to one IgG. Immunol. Today 21, 310–312 (2000).

    Article  CAS  PubMed  Google Scholar 

  33. Zhang, Y. et al. Crystal structure of the extracellular domain of a human FcγRIII. Immunity 13, 387–395 (2000).

    Article  CAS  PubMed  Google Scholar 

  34. Kinet, J. P. The high-affinity IgE receptor (FcɛRI): from physiology to pathology. Annu. Rev. Immunol. 17, 931–972 (1999).

    Article  CAS  PubMed  Google Scholar 

  35. Ghazizadeh, S., Bolen, J. B. & Fleit, H. B. Physical and functional association of Src-related protein tyrosine kinases with FcγRII in monocytic THP-1 cells. J. Biol. Chem. 269, 8878–8884 (1994).

    Article  CAS  PubMed  Google Scholar 

  36. Wang, A. V., Scholl, P. R. & Geha, R. S. Physical and functional association of the high affinity immunoglobulin G receptor (FcγRI) with the kinases Hck and Lyn. J. Exp. Med. 180, 1165–1170 (1994).

    Article  CAS  PubMed  Google Scholar 

  37. Kiener, P. A. et al. Cross-linking of Fcγ receptor I (FcγRI) and receptor II (FcγRII) on monocytic cells activates a signal transduction pathway common to both Fc receptors that involves the stimulation of p72 Syk protein tyrosine kinase. J. Biol. Chem. 268, 24442–24448 (1993).

    Article  CAS  PubMed  Google Scholar 

  38. 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).

    Article  CAS  PubMed  Google Scholar 

  39. Rankin, B. M., Yocum, S. A., Mittler, R. S. & Kiener, P. A. Stimulation of tyrosine phosphorylation and calcium mobilization by Fcγ receptor cross-linking. Regulation by the phosphotyrosine phosphatase CD45. J. Immunol. 150, 605–616 (1993).

    CAS  PubMed  Google Scholar 

  40. Liao, F., Shin, H. S. & Rhee, S. G. Tyrosine phosphorylation of phospholipase C-γ 1 induced by cross-linking of the high-affinity or low-affinity Fc receptor for IgG in U937 cells. Proc. Natl Acad. Sci. USA 89, 3659–3663 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Takai, T., Li, M., Sylvestre, D., Clynes, R. & Ravetch, J. V. FcRγ chain deletion results in pleiotrophic effector cell defects. Cell 76, 519–529 (1994). By generating the γ-chain knockout mouse these authors show the central importance of this molecule for the function of activating FcRs.

    Article  CAS  PubMed  Google Scholar 

  42. Clynes, R. & Ravetch, J. V. Cytotoxic antibodies trigger inflammation through Fc receptors. Immunity 3, 21–26 (1995).

    Article  CAS  PubMed  Google Scholar 

  43. Park, S. Y. et al. Resistance of Fc receptor-deficient mice to fatal glomerulonephritis. J. Clin. Invest. 102, 1229–1238 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Sylvestre, D. L. & Ravetch, J. V. Fc receptors initiate the Arthus reaction: redefining the inflammatory cascade. Science 265, 1095–1098 (1994).

    Article  CAS  PubMed  Google Scholar 

  45. Zhang, M. et al. Activating Fc receptors are required for antitumor efficacy of the antibodies directed toward CD25 in a murine model of adult T-cell leukemia. Cancer Res. 64, 5825–5829 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. Azeredo da Silveira, S. et al. Complement activation selectively potentiates the pathogenicity of the IgG2b and IgG3 isotypes of a high affinity anti-erythrocyte autoantibody. J. Exp. Med. 195, 665–672 (2002).

    Article  CAS  PubMed  Google Scholar 

  47. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Nimmerjahn, F. & Ravetch, J. V. The antiinflammatory activity of IgG: the intravenous IgG paradox. J. Exp. Med. 204, 11–15 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ravetch, J. V. & Clynes, R. A. Divergent roles for Fc receptors and complement in vivo. Annu. Rev. Immunol. 16, 421–432 (1998).

    Article  CAS  PubMed  Google Scholar 

  50. Sylvestre, D. et al. Immunoglobulin G-mediated inflammatory responses develop normally in complement-deficient mice. J. Exp. Med. 184, 2385–2392 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Uchida, J. et al. The innate mononuclear phagocyte network depletes B lymphocytes through Fc receptor-dependent mechanisms during anti-CD20 antibody immunotherapy. J. Exp. Med. 199, 1659–1669 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kumar, V. et al. Cell-derived anaphylatoxins as key mediators of antibody-dependent type II autoimmunity in mice. J. Clin. Invest. 116, 512–520 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Schmidt, R. E. & Gessner, J. E. Fc receptors and their interaction with complement in autoimmunity. Immunol. Lett. 100, 56–67 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. Barnes, N. et al. FcγRI-deficient mice show multiple alterations to inflammatory and immune responses. Immunity 16, 379–389 (2002).

    Article  CAS  PubMed  Google Scholar 

  55. Bevaart, L. et al. Direct targeting of genetically modified tumour cells to FcγRI triggers potent tumour cytotoxicity. Br. J. Haematol. 132, 317–325 (2006).

    Article  CAS  PubMed  Google Scholar 

  56. Fossati-Jimack, L. et al. Markedly different pathogenicity of four immunoglobulin G isotype-switch variants of an antierythrocyte autoantibody is based on their capacity to interact in vivo with the low-affinity Fcγ receptor III. J. Exp. Med. 191, 1293–1302 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. 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).

    Article  CAS  PubMed  Google Scholar 

  58. Hazenbos, W. L. et al. Impaired IgG-dependent anaphylaxis and Arthus reaction in FcγRIII (CD16) deficient mice. Immunity 5, 181–188 (1996).

    Article  CAS  PubMed  Google Scholar 

  59. Ji, H. et al. Arthritis critically dependent on innate immune system players. Immunity 16, 157–168 (2002).

    Article  CAS  PubMed  Google Scholar 

  60. Meyer, D. et al. FcγRIII (CD16)-deficient mice show IgG isotype-dependent protection to experimental autoimmune hemolytic anemia. Blood 92, 3997–4002 (1998).

    Article  CAS  PubMed  Google Scholar 

  61. Cartron, G. et al. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcγRIIIa gene. Blood 99, 754–758 (2002).

    Article  CAS  PubMed  Google Scholar 

  62. Weng, W. K., Czerwinski, D., Timmerman, J., Hsu, F. J. & Levy, R. Clinical outcome of lymphoma patients after idiotype vaccination is correlated with humoral immune response and immunoglobulin G Fc receptor genotype. J. Clin. Oncol. 22, 4717–4724 (2004).

    Article  CAS  PubMed  Google Scholar 

  63. Weng, W. K. & Levy, R. Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J. Clin. Oncol. 21, 3940–3947 (2003). References 61–63 demonstrate the importance of FcγRs as effector molecules for antibody therapy of cancer in humans.

    Article  CAS  PubMed  Google Scholar 

  64. Bussel, J. B. Fc receptor blockade and immune thrombocytopenic purpura. Semin. Hematol. 37, 261–266 (2000).

    Article  CAS  PubMed  Google Scholar 

  65. Stuart, L. M. & Ezekowitz, R. A. Phagocytosis: elegant complexity. Immunity 22, 539–550 (2005).

    Article  CAS  PubMed  Google Scholar 

  66. Swanson, J. A. & Hoppe, A. D. The coordination of signaling during Fc receptor-mediated phagocytosis. J. Leukoc. Biol. 76, 1093–1103 (2004).

    Article  CAS  PubMed  Google Scholar 

  67. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Goodnow, C. C., Sprent, J., de St Groth, B. F. & Vinuesa, C. G. Cellular and genetic mechanisms of self tolerance and autoimmunity. Nature 435, 590–597 (2005).

    Article  CAS  PubMed  Google Scholar 

  69. Amigorena, S. et al. Cytoplasmic domain heterogeneity and functions of IgG Fc receptors in B lymphocytes. Science 256, 1808–1812 (1992).

    Article  CAS  PubMed  Google Scholar 

  70. Muta, T. et al. A 13-amino-acid motif in the cytoplasmic domain of FcγRIIB modulates B-cell receptor signalling. Nature 369, 340 (1994). This study, together with reference 69, was the first to identify and characterize the function of the ITIMs in FcγRIIB.

    Article  CAS  PubMed  Google Scholar 

  71. Nitschke, L. & Tsubata, T. Molecular interactions regulate BCR signal inhibition by CD22 and CD72. Trends Immunol. 25, 543–550 (2004).

    Article  CAS  PubMed  Google Scholar 

  72. 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).

    Article  CAS  PubMed  Google Scholar 

  73. Ono, M. et al. Deletion of SHIP or SHP-1 reveals two distinct pathways for inhibitory signalling. Cell 90, 293–301 (1997).

    Article  CAS  PubMed  Google Scholar 

  74. Pearse, R. N. et al. SHIP recruitment attenuates FcγRIIB-induced B cell apoptosis. Immunity 10, 753–760 (1999).

    Article  CAS  PubMed  Google Scholar 

  75. Tzeng, S. J., Bolland, S., Inabe, K., Kurosaki, T. & Pierce, S. K. The B cell inhibitory Fc receptor triggers apoptosis by a novel c-Abl-family kinase dependent pathway. J. Biol. Chem. 22, 22 (2005).

    Google Scholar 

  76. Radbruch, A. et al. Competence and competition: the challenge of becoming a long-lived plasma cell. Nature Rev. Immunol. 6, 741–750 (2006).

    Article  CAS  Google Scholar 

  77. Odendahl, M. et al. Generation of migratory antigen-specific plasma blasts and mobilization of resident plasma cells in a secondary immune response. Blood 105, 1614–1621 (2005).

    Article  CAS  PubMed  Google Scholar 

  78. Ravetch, J. V. & Nussenzweig, M. Killing some to make way for others. Nature Immunol. 8, 337–339 (2007).

    Article  CAS  Google Scholar 

  79. Xiang, Z. et al. FcγRIIb controls bone marrow plasma cell persistence and apoptosis. Nature Immunol. 8, 419–429 (2007). The authors demonstrate that plasma cells are susceptible to FcγRIIB-triggered apoptosis; by contrast, plasma cells from autoimmune mice were more resistant, which might explain their higher abundance in these strains.

    Article  CAS  Google Scholar 

  80. Dudziak, D. et al. Differential antigen processing by dendritic cell subsets in vivo. Science 315, 107–111 (2007).

    Article  CAS  PubMed  Google Scholar 

  81. Hawiger, D. et al. Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. J. Exp. Med. 194, 769–779 (2001). This is one of the first studies demonstrating that DCs can functionally inactivate antigen-specific T cells under steady state conditions in vivo.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Hawiger, D., Masilamani, R. F., Bettelli, E., Kuchroo, V. K. & Nussenzweig, M. C. Immunological unresponsiveness characterized by increased expression of CD5 on peripheral T cells induced by dendritic cells in vivo. Immunity 20, 695–705 (2004).

    Article  CAS  PubMed  Google Scholar 

  83. Kretschmer, K. et al. Inducing and expanding regulatory T cell populations by foreign antigen. Nature Immunol. 6, 1219–1227 (2005).

    Article  CAS  Google Scholar 

  84. Steinman, R. M. et al. Dendritic cell function in vivo during the steady state: a role in peripheral tolerance. Ann. NY Acad. Sci. 987, 15–25 (2003).

    Article  CAS  PubMed  Google Scholar 

  85. Schuurhuis, D. H., Fu, N., Ossendorp, F. & Melief, C. J. Ins and outs of dendritic cells. Int. Arch. Allergy Immunol. 140, 53–72 (2006).

    Article  PubMed  Google Scholar 

  86. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Dhodapkar, K. M., Krasovsky, J., Williamson, B. & Dhodapkar, M. V. Antitumor monoclonal antibodies enhance cross-presentation of cellular antigens and the generation of myeloma-specific killer T cells by dendritic cells. J. Exp. Med. 195, 125–133 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Groh, V. et al. Efficient cross-priming of tumor antigen-specific T cells by dendritic cells sensitized with diverse anti-MICA opsonized tumor cells. Proc. Natl Acad. Sci. USA 102, 6461–6466 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Rafiq, K., Bergtold, A. & Clynes, R. Immune complex-mediated antigen presentation induces tumor immunity. J. Clin. Invest. 110, 71–79 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Schuurhuis, D. H. et al. Immune complex-loaded dendritic cells are superior to soluble immune complexes as antitumor vaccine. J. Immunol. 176, 4573–4580 (2006).

    Article  CAS  PubMed  Google Scholar 

  91. 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).

    Article  CAS  PubMed  Google Scholar 

  92. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Boruchov, A. M. et al. Activating and inhibitory IgG Fc receptors on human DCs mediate opposing functions. J. Clin. Invest. 115, 2914–2923 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. 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). References 92–94 demonstrate the important role of FcγRIIB as a regulator of DC activity and its potential to modulate adaptive immune responses.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Nimmerjahn, F. & Ravetch, J. V. Antibodies, Fc receptors and cancer. Curr. Opin. Immunol. 19, 239–245 (2007).

    Article  CAS  PubMed  Google Scholar 

  96. Lazar, G. A. et al. Engineered antibody Fc variants with enhanced effector function. Proc. Natl Acad. Sci. USA 103, 4005–4010 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Shields, R. L. et al. High resolution mapping of the binding site on human IgG1 for FcγRI, FcγRII, FcγRIII, and FcRn and design of IgG1 variants with improved binding to the FcγR. J. Biol. Chem. 276, 6591–6604 (2001).

    Article  CAS  PubMed  Google Scholar 

  98. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Bergtold, A., Gavhane, A., D'Agati, V., Madaio, M. & Clynes, R. FcR-bearing myeloid cells are responsible for triggering murine lupus nephritis. J. Immunol. 177, 7287–7295 (2006).

    Article  CAS  PubMed  Google Scholar 

  101. Arnold, J. N., Wormald, M. R., Sim, R. B., Rudd, P. M. & Dwek, R. A. The impact of glycosylation on the biological function and structure of human immunoglobulins. Annu. Rev. Immunol. 25, 21–50 (2007).

    Article  CAS  PubMed  Google Scholar 

  102. Ferrara, C., Stuart, F., Sondermann, P., Brunker, P. & Umana, P. The carbohydrate at FcγRIIIa Asn-162. An element required for high affinity binding to non-fucosylated IgG glycoforms. J. Biol. Chem. 281, 5032–5036 (2006). This study suggests that the differential impact of fucose on binding to different Fcγ-receptors is dependent on FcγR glycosylation.

    Article  CAS  PubMed  Google Scholar 

  103. Shields, R. L. et al. Lack of fucose on human IgG1 N-linked oligosaccharide improves binding to human FcγRIII and antibody-dependent cellular toxicity. J. Biol. Chem. 277, 26733–26740 (2002).

    Article  CAS  PubMed  Google Scholar 

  104. Shinkawa, T. et al. The absence of fucose but not the presence of galactose or bisecting N-acetylglucosamine of human IgG1 complex-type oligosaccharides shows the critical role of enhancing antibody-dependent cellular cytotoxicity. J. Biol. Chem. 278, 3466–3473 (2003).

    Article  CAS  PubMed  Google Scholar 

  105. Arnold, J. N., Dwek, R. A., Rudd, P. M. & Sim, R. B. Mannan binding lectin and its interaction with immunoglobulins in health and in disease. Immunol. Lett. 106, 103–110 (2006).

    Article  CAS  PubMed  Google Scholar 

  106. Bond, A., Cooke, A. & Hay, F. C. Glycosylation of IgG, immune complexes and IgG subclasses in the MRL-lpr/lpr mouse model of rheumatoid arthritis. Eur. J. Immunol. 20, 2229–2233 (1990).

    Article  CAS  PubMed  Google Scholar 

  107. Mizuochi, T., Hamako, J., Nose, M. & Titani, K. Structural changes in the oligosaccharide chains of IgG in autoimmune MRL/Mp-lpr/lpr mice. J. Immunol. 145, 1794–1798 (1990).

    CAS  PubMed  Google Scholar 

  108. Malhotra, R. et al. Glycosylation changes of IgG associated with rheumatoid arthritis can activate complement via the mannose-binding protein. Nature Med. 1, 237–243 (1995).

    Article  CAS  PubMed  Google Scholar 

  109. Nimmerjahn, F., Anthony, R. M. & Ravetch, J. V. Agalactosylated IgG antibodies depend on cellular Fc receptors for in vivo activity. Proc. Natl Acad. Sci. USA 104, 8433–8437 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Kaneko, Y., Nimmerjahn, F. & Ravetch, J. V. Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science 313, 670–673 (2006). The authors demonstrate that the sialic-acid-rich fraction of IVIG is responsible for its anti-inflammatory activity.

    Article  CAS  PubMed  Google Scholar 

  111. 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).

    Article  CAS  PubMed  Google Scholar 

  112. Debre, M. et al. Infusion of Fcγ fragments for treatment of children with acute immune thrombocytopenic purpura. Lancet 342, 945–949 (1993). This was the first study to show that the IgG Fc-fragment is responsible for mediating the anti-inflammatory activity of IVIG in human patients.

    Article  CAS  PubMed  Google Scholar 

  113. Samuelsson, A., Towers, T. L. & Ravetch, J. V. Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor. Science 291, 484–486 (2001).

    Article  CAS  PubMed  Google Scholar 

  114. Park-Min, K. H. et al. FcγRIII-dependent inhibition of interferon-γ responses mediates suppressive effects of intravenous immune globulin. Immunity 26, 67–78 (2007).

    Article  CAS  PubMed  Google Scholar 

  115. Siragam, V. et al. Intravenous immunoglobulin ameliorates ITP via activating Fc γ receptors on dendritic cells. Nature Med. 12, 688–692 (2006).

    Article  CAS  PubMed  Google Scholar 

  116. McGaha, T. L., Sorrentino, B. & Ravetch, J. V. Restoration of tolerance in lupus by targeted inhibitory receptor expression. Science 307, 590–593 (2005). This study demonstrates the therapeutic potential of increasing FcγRIIB expression on B cells to restore tolerance in autoimmune-prone mouse strains.

    Article  CAS  PubMed  Google Scholar 

  117. Vitetta, E. S. & Ghetie, V. F. Immunology. Considering therapeutic antibodies. Science 313, 308–309 (2006).

    Article  CAS  PubMed  Google Scholar 

  118. Li, M., Wirthmueller, U. & Ravetch, J. V. Reconstitution of human FcγRIII cell type specificity in transgenic mice. J. Exp. Med. 183, 1259–1263 (1996).

    Article  CAS  PubMed  Google Scholar 

  119. Bolland, S. & Ravetch, J. V. Spontaneous autoimmune disease in FcγRIIB-deficient mice results from strain-specific epistasis. Immunity 13, 277–285 (2000).

    Article  CAS  PubMed  Google Scholar 

  120. Bolland, S., Yim, Y. S., Tus, K., Wakeland, E. K. & Ravetch, J. V. Genetic modifiers of systemic lupus erythematosus in FcγRIIB−/− mice. J. Exp. Med. 195, 1167–1174 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Fukuyama, H., Nimmerjahn, F. & Ravetch, J. V. The inhibitory Fcγ receptor modulates autoimmunity by limiting the accumulation of immunoglobulin G+ anti-DNA plasma cells. Nature Immunol. 6, 99–106 (2005).

    Article  CAS  Google Scholar 

  122. Takai, T., Ono, M., Hikida, M., Ohmori, H. & Ravetch, J. V. Augmented humoral and anaphylactic responses in FcγRII-deficient mice. Nature 379, 346–349 (1996). This study describes the generation of the Fcgriib -knockout mouse, which provided the first clear evidence of the importance of this protein in regulating immune responses.

    Article  CAS  PubMed  Google Scholar 

  123. Paul, E., Nelde, A., Verschoor, A. & Carroll, M. C. Follicular exclusion of autoreactive B cells requires FcγRIIb. Int. Immunol. 19, 365–373 (2007).

    Article  CAS  PubMed  Google Scholar 

  124. Nakamura, A. et al. Fcγ receptor IIB-deficient mice develop Goodpasture's syndrome upon immunization with type IV collagen: a novel murine model for autoimmune glomerular basement membrane disease. J. Exp. Med. 191, 899–906 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Jiang, Y. et al. Polymorphisms in IgG Fc receptor IIB regulatory regions associated with autoimmune susceptibility. Immunogenetics 51, 429–435 (2000).

    Article  CAS  PubMed  Google Scholar 

  126. Jiang, Y. et al. Genetically determined aberrant down-regulation of FcγRIIB1 in germinal center B cells associated with hyper-IgG and IgG autoantibodies in murine systemic lupus erythematosus. Int. Immunol. 11, 1685–1691 (1999).

    Article  CAS  PubMed  Google Scholar 

  127. Pritchard, N. R. et al. Autoimmune-prone mice share a promoter haplotype associated with reduced expression and function of the Fc receptor FcγRII. Curr. Biol. 10, 227–230 (2000).

    Article  CAS  PubMed  Google Scholar 

  128. Xiu, Y. et al. Transcriptional regulation of Fcgr2b gene by polymorphic promoter region and its contribution to humoral immune responses. J. Immunol. 169, 4340–4346 (2002).

    Article  CAS  PubMed  Google Scholar 

  129. Holmes, M. C. & Burnet, F. M. The natural history of autoimmune disease in Nzb mice. A comparison with the pattern of human autoimmune manifestations. Ann. Intern. Med. 59, 265–276 (1963).

    Article  CAS  PubMed  Google Scholar 

  130. Hoyer, B. F. et al. Short-lived plasmablasts and long-lived plasma cells contribute to chronic humoral autoimmunity in NZB/W mice. J. Exp. Med. 199, 1577–1584 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Blank, M. C. et al. Decreased transcription of the human FCGR2B gene mediated by the −343 G/C promoter polymorphism and association with systemic lupus erythematosus. Hum. Genet. 117, 220–227 (2005).

    Article  CAS  PubMed  Google Scholar 

  132. Su, K. et al. A promoter haplotype of the immunoreceptor tyrosine-based inhibitory motif-bearing FcγRIIb alters receptor expression and associates with autoimmunity. II. Differential binding of GATA4 and Yin-Yang1 transcription factors and correlated receptor expression and function. J. Immunol. 172, 7192–7199 (2004).

    Article  CAS  PubMed  Google Scholar 

  133. Su, K. et al. A promoter haplotype of the immunoreceptor tyrosine-based inhibitory motif-bearing FcγRIIb alters receptor expression and associates with autoimmunity. I. Regulatory FCGR2B polymorphisms and their association with systemic lupus erythematosus. J. Immunol. 172, 7186–7191 (2004).

    Article  CAS  PubMed  Google Scholar 

  134. Floto, R. A. et al. Loss of function of a lupus-associated FcγRIIb polymorphism through exclusion from lipid rafts. Nature Med. 11, 1056–1058 (2005).

    Article  CAS  PubMed  Google Scholar 

  135. Kono, H. et al. FcγRIIB Ile232Thr transmembrane polymorphism associated with human systemic lupus erythematosus decreases affinity to lipid rafts and attenuates inhibitory effects on B cell receptor signaling. Hum. Mol. Genet. 14, 2881–2892 (2005). In references 134 and 135, the authors elegantly demonstrate that the FcγRIIB I232T allele which is associated with systemic lupus erythematosus in humans is functionally impaired owing to its inefficient association with lipid rafts.

    Article  CAS  PubMed  Google Scholar 

  136. Mackay, M. et al. Selective dysregulation of the FcγIIB receptor on memory B cells in SLE. J. Exp. Med. 203, 2157–2164 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would especially like to thank P. Sondermann (Roche), who generously provided the structural data and pictures concerning the antibody FcR interaction and for his critical reading of the manuscript. Similarly, we thank. S. Bolland for suggestions on the manuscript. This work was supported by grants from the German Research Foundation (DFG) and the Bavarian Genome Network (BayGene) to F.N., and by grants from the National Institutes of Health (NIH), USA, and E. Ludwig to J.V.R. We apologize to all colleagues whose important work was not directly cited due to space limitations. These references can be found in the numerous review articles referred to in this Review.

Author information

Authors and Affiliations

Authors

Related links

FURTHER INFORMATION

Falk Nimmerjahn's homepage

Glossary

Regulatory T cells

A T cell subset that is capable of suppressing the activity of other antigen-specific T cells including autoreactive T cells. Depletion of regulatory T cells results in the loss of peripheral tolerance and the development of autoimmune disease.

Immunoreceptor tyrosine-based activation motif

(ITAM). A short peptide motif containing tyrosine residues that is found in the cytoplasmic tail of several signalling adaptor proteins such as the common γ- or CD3ζ-chain. It is necessary to recruit proteins that are involved in triggering activating signalling proteins. The consensus sequence is Tyr-X-X-(Leu/Ile)-X6–8-Tyr-X-X-(Leu/Ile), where X denotes any amino acid.

Immunoreceptor tyrosine-based inhibitory motif

(ITIM). A short peptide motif containing a tyrosine residue that is found in the cytoplasmic portion of FcγRIIB and other regulatory proteins such as CD22 or CD72 that is necessary to recruit negative regulatory signalling proteins. The consensus sequence is (Ile/Val/Leu/Ser)-X-Tyr-X-X-(Leu/Val), where X denotes any amino acid.

Type I transmembrane glycoproteins

Glycoproteins of which the carboxyterminus of the polypeptide chain is located in the cytosol whereas the aminoterminus is exposed to the extracelluar space.

Neonatal FcR

(FcRn). FcRn is unrelated to classical FcRs and binds to a different region in the antibody Fc fragment. Structurally it is related to the family of MHC class I molecules and is responsible for regulating IgG half-life.

Dyad symmetry

The symmetrical arrangement of the repetitive structural elements an antibody molecule is composed of.

Complement cascade

There are three independent pathways that can lead to the activation of the complement cascade. The classical pathway is activated via C1q binding to immune complexes, the alternative pathway is triggered by direct C3 activation, and the lectin pathway is initiated by mannose-binding lectin (MBL) binding to the surface of microorganisms.

K/BxN serum transfer arthritis model

A mouse strain formed by crossing non-obese diabetic (NOD)/Lt mice with KRN T-cell-receptor-transgenic mice on the C57BL/6 background. As the KRN receptor on the T cells recognizes a peptide from the autoantigen glucose-6-phosphate isomerase, these mice develop an arthritis that is mediated, and transferable, by circulating antibody against glucose-6-phosphate isomerase.

Class switching

If B cells recognize their cognate antigen in the spleen a portion of them switch the expression of their B-cell receptor from IgM to other isotypes such as IgG, IgA or IgE. The decision of which isotype is generated is strongly influenced by the specific cytokine milieu and other cells such as T-helper cells.

Pleckstrin homology (PH)-domain

An amino acid motif that enables proteins to recognize phosphatidylinositol-3,4,5-trisphosphate.

Plasmablasts

A short lived, dividing cell population that can develop from any type of activated B cell and that is characterized by its capacity to secrete antibodies.

Plasma cells

Terminally differentiated quiescent B cells that develop from plasmablasts and are characterized by their capacity to secrete large amounts of antibodies.

Affinity maturation

A process in which random mutations are introduced into the variable regions of the B-cell receptor genes followed by selection of cells with a higher affinity for the cognate antigen. This process takes place in specialized compartments of the spleen, which are known as germinal centres.

Competitive dislocation

This term refers to the competition of newly developed plasma cells for anatomical niches in the bone marrow that are already occupied by plasma cells that were generated during previous immune responses.

Cross presentation

The uptake of proteins by dendritic cells results in their degradation into small peptides in endosomal and lysosomal compartments and peptide presentation on MHC class II molecules. Cross presentation describes a process in which endocytosed material escapes into the cytoplasm where it is degraded by the proteasome followed by presentation on MHC class I molecules.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nimmerjahn, F., Ravetch, J. Fcγ receptors as regulators of immune responses. Nat Rev Immunol 8, 34–47 (2008). https://doi.org/10.1038/nri2206

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri2206

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing