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The complement system in regulation of adaptive immunity

Nature Immunology volume 5, pages 981–986 (2004)Cite this article

Abstract

The serum complement system, which represents a chief component of innate immunity, not only participates in inflammation but also acts to enhance the adaptive immune response. Specific activation of complement via innate recognition proteins or secreted antibody releases cleavage products that interact with a wide range of cell surface receptors found on myeloid, lymphoid and stromal cells. This intricate interaction among complement activation products and cell surface receptors provides a basis for the regulation of both B and T cell responses. This review highlights fundamental events, explaining how complement links innate and adaptive immunity as well as describing more recent studies on how this large family of proteins functions locally in peripheral lymph nodes to enhance B and T cell responses.

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Figure 1: Complement receptors are important in the regulation of B lymphocyte differentiation at five stages.
Figure 2: Complement enhances B cell response to herpes simplex virus 1 introduced intradermally.

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References

  1. Bordet, J. & Gengou, O. Sur l'existence de substances sensibilisatrices dans la plupart des serum antimicrobiens. Ann. Inst. Pasteur 15, 289–302 (1901).

    Google Scholar 

  2. Hosea, S.W., Brown, E.J. & Frank, M.M. The critical role of complement in experimental pneumococcal sepsis. J. Infect. Dis. 142, 903–909 (1980).

    Article  CAS  Google Scholar 

  3. Reid, K.B.M. & Porter, R.R. The proteolytic activation systems of complement. Annu. Rev. Biochem. 50, 433–464 (1981).

    Article  CAS  Google Scholar 

  4. Fearon, D.T. & Carroll, M.C. Regulation of B lymphocyte responses to foreign and self-antigens by the CD19/CD21 complex. Annu. Rev. Immunol. 18, 393–422 (2000).

    Article  CAS  Google Scholar 

  5. Barton, G.M. & Medzhitov, R. Toll-like receptors and their ligands. Curr. Top. Microbiol. Immunol. 270, 81–92 (2002).

    CAS  PubMed  Google Scholar 

  6. Janeway, C.A. Jr. & Medzhitov, R. Lipoproteins take their toll on the host. Curr. Biol. 9, 879–882 (1999).

    Article  Google Scholar 

  7. Epstein, J., Eichbaum, Q.E., Sheriff, S. & Ezekowitz, R.A.B. The collectins in innate immunity. Curr. Opin. Immunol. 8, 29–35 (1996).

    Article  CAS  Google Scholar 

  8. Matsushita, M. & Fujita, T. The role of ficolins in innate immunity. Immunobiol. 205, 490–497 (2002).

    Article  CAS  Google Scholar 

  9. Szalai, A.J., Agrawal, A., Greenhough, T.J. & Volanakis, J.E. C-reactive protein: structural biology, gene expression, and host defense. Immunol. Res. 16, 127–136 (1997).

    Article  CAS  Google Scholar 

  10. Korb, L.C. & Ahearn, J.M. C1q binds directly and specifically to surface blebs of apoptotic keratinocytes. J. Immunol. 158, 4525–4528 (1997).

    CAS  PubMed  Google Scholar 

  11. Taylor, P.R. et al. A hierarchical role for classical pathway complement proteins in the clearance of apoptotic cells in vivo. J. Exp. Med. 192, 359–366 (2000).

    Article  CAS  Google Scholar 

  12. Boes, M., Prodeus, A., Schmidt, T., Carroll, M.C. & Chen, J. A critical role of natural IgM in immediate response against systemic bacterial infection. J. Exp. Med. 188, 2381–2386 (1998).

    Article  CAS  Google Scholar 

  13. Baumgarth, N. et al. B1 and B2 cell-derived immunoglobulin M antibodies are non-redundant components of the protective response to influenza virus infection. J. Exp. Med. 192, 271–280 (2000).

    Article  CAS  Google Scholar 

  14. Reid, R.R. et al. Endotoxin shock in antibody-deficient mice: unraveling the role of natural antibody and complement in the clearance of lipopolysaccharide. J. Immunol. 159, 970–975 (1997).

    CAS  PubMed  Google Scholar 

  15. Reid, K. & Turner, M. Mammalian lectins in activation and clearance mechanisms involving the complement system. Semin. Immunopathol. 15, 307–326 (1994).

    Article  CAS  Google Scholar 

  16. Fujita, T., Matsushita, M. & Endo, Y. The lectin-complement pathway—its role in innate immunity and evolution. Immunol. Rev. 198, 185–202 (2004).

    Article  CAS  Google Scholar 

  17. Stahl, P.D. & Ezekowitz, R.A. The mannose receptor is a pattern recognition receptor involved in host defense. Curr. Opin. Immunol. 10, 50–55 (1998).

    Article  CAS  Google Scholar 

  18. Fearon, D.T. & Austen, K.F. Initiation of C3 cleavage in the alternative complement pathway. J. Immunol. 115, 1357–1361 (1975).

    CAS  PubMed  Google Scholar 

  19. Daha, M.R., Fearon, D.T. & Austen, K.F. C3 requirements for formation of alternative pathway C5 convertase. J. Immunol. 117, 630–634 (1976).

    CAS  PubMed  Google Scholar 

  20. Liszewski, M.K., Post, T.W. & Atkinson, J.P. Membrane cofactor protein (MCP or CD46): newest member of the regulators of complement activation gene cluster. Annu. Rev. Immunol. 9, 431–455 (1991).

    Article  CAS  Google Scholar 

  21. Fearon, D.T. & Carter, R.H. The CD19/CR2/TAPA-1 Complex of B lymphocytes: linking natural to acquired immunity. Annu. Rev. Immunol. 13, 127–149 (1995).

    Article  CAS  Google Scholar 

  22. Fearon, D.T. & Locksley, R.M. The instructive role of innate immunity in the acquired immune response. Science 272, 50–54 (1996).

    Article  CAS  Google Scholar 

  23. Nussenzweig, V., Bianco, C., Dukor, P. & Eden, A. Receptors for C3 on B lymphocytes: possible role in the immune response. Progress in Immunology Vol. 59 (Amos, B. ed.) 73–81 (Academic, New York, 1971).

    Chapter  Google Scholar 

  24. Papamichail, M. et al. Complement dependence of localization of aggregated IgG in germinal centers. Scand. J. Immunol. 4, 343–347 (1975).

    Article  CAS  Google Scholar 

  25. Pepys, M.B. Role of complement in the induction of immunological responses. Transpl. Rev. 32, 93–120 (1976).

    CAS  Google Scholar 

  26. Law, S.K., Lichtenberg, N.A. & Levine, R.P. Covalent binding and hemolytic activity of complement proteins. Proc. Natl. Acad. Sci. USA 77, 7194–7198 (1980).

    Article  CAS  Google Scholar 

  27. Tack, B.F. et al. Evidence for presence of an internal thiolester bond in third component of human complement. Proc. Natl. Acad. Sci. USA 77, 5764–5768 (1980).

    Article  CAS  Google Scholar 

  28. Isenman, D.E. The role of the thioester bond in C3 and C4 in the determination of the conformational and functional states of the molecule. Ann. NY Acad. Sci. 421, 277–290 (1983).

    Article  CAS  Google Scholar 

  29. Lachmann, P.J. & Hughes-Jones, N.C. Initiation of complement activation. Spring. Semin. Immunopathol. 7, 143–162 (1984).

    Article  CAS  Google Scholar 

  30. Molina, H., Kinoshita, T., Webster, C.B. & Holers, V.M. Analysis of C3b/C3d binding sites and factor I cofactor regions within mouse complement receptors 1 and 2. J. Immunol. 153, 789–795 (1994).

    CAS  PubMed  Google Scholar 

  31. Kurtz, C.B., O'Toole, E., Christensen, S.M. & Weis, J.H. The murine complement receptor gene family. IV. Alternative splicing of Cr2 gene transcripts predicts two distinct gene products that share homologous domains with both human CR2 and CR1. J. Immunol. 144, 3581–3591 (1990).

    CAS  PubMed  Google Scholar 

  32. Molina, H. et al. A molecular and immunochemical characterization of mouse CR2. J. Immunol. 145, 2974–2983 (1990).

    CAS  PubMed  Google Scholar 

  33. Matsumoto, A.K. et al. Intersection of the complement and immune systems: a signal transduction complex of the B lymphocyte containing complement receptor type 2 and CD19. J. Exp. Med. 173, 55–64 (1991).

    Article  CAS  Google Scholar 

  34. Carter, R.H. & Fearon, D.T. CD19:Lowering the threshold for antigen receptor stimulation of B lymphocytes. Science 256, 105–107 (1992).

    Article  CAS  Google Scholar 

  35. Fang, Y., Xu, C., Fu, Y., Holers, V.M. & Molina, H. Expression of complement receptors 1 and 2 on follicular dendritic cells is necessary for the generation of a strong antigen-specific IgG response. J. Immunol. 160, 5273–5279 (1998).

    CAS  PubMed  Google Scholar 

  36. Cyster, J.G. et al. Follicular stromal cells and lymphocyte homing to follicles. Immunol Rev. 176, 181–193 (2000).

    Article  CAS  Google Scholar 

  37. Liu, Y.J., Grouard, G., de Bouteiller, O. & Banchereau, J. Follicular dendritic cells and germinal centers. Int. Rev. Cytol. 166, 139–179 (1996).

    Article  CAS  Google Scholar 

  38. Barrington, R.A., Pozdnyakova, O., Zafari, M.R., Benjamin, C.D. & Carroll, M.C. B lymphocyte memory: role of stromal cell complement and FcγRIIB receptors. J. Exp. Med. 196, 1189–1199 (2002).

    Article  CAS  Google Scholar 

  39. Cutler, A. et al. (1998) T cell-dependent immune response in C1q-deficient mice: defective interferon γ production by antigen-specific T cells. J. Exp. Med. 187, 1789–1797 (2002).

    Article  Google Scholar 

  40. Fischer, M. et al. Regulation of the B cell response to T-dependent antigens by classical pathway complement. J. Immunol. 157, 549–556 (1996).

    CAS  PubMed  Google Scholar 

  41. Ahearn, J. et al. Disruption of the Cr2 locus results in a reduction in B-1a cells and in an impaired B cell response to T-dependent antigen. Immunity 4, 251–262 (1996).

    Article  CAS  Google Scholar 

  42. Molina, H. et al. Markedly impaired humoral immune response in mice deficient in complement receptors 1 and 2. Proc. Natl. Acad. Sci. USA 93, 3357–3361 (1996).

    Article  CAS  Google Scholar 

  43. Carroll, M.C. The complement system in B cell regulation. Mol. Immunol. 41, 141–146 (2004).

    Article  CAS  Google Scholar 

  44. Carsetti, R., Kohler, G. & Lamers, M.C. Transitional B cells are the target of negative selection in the B cell compartment. J. Exp. Med. 181, 2129–2140 (1995).

    Article  CAS  Google Scholar 

  45. Norvell, A., Mandik, L. & Monroe, J.G. Engagement of the antigen receptor on immature murine B lymphocytes results in death by apoptosis. J. Immunol. 154, 4404–4413 (1995).

    CAS  PubMed  Google Scholar 

  46. Karlsson, M.C. et al. Macrophages control the retention and trafficking of B lymphocytes in the splenic marginal zone. J. Exp. Med. 198, 333–340 (2003).

    Article  CAS  Google Scholar 

  47. Pozdnyakova, O., Guttormsen, H.K., Lalani, F.N., Carroll, M.C. & Kasper, D.L. Impaired antibody response to group B streptococcal type III capsular polysaccharide in C3- and complement receptor 2-deficient mice. J. Immunol. 170, 84–90 (2003).

    Article  CAS  Google Scholar 

  48. Hardy, R.R. & Hayakawa, K. B cell development pathways. Annu. Rev. Immunol. 19, 595–621 (2001).

    Article  CAS  Google Scholar 

  49. Arnold, L., Pennell, C., McCray, S. & Clarke, S. Development of B-1 cells: segregation of phosphatidyl choline specific B cells to the B-1 population occurs after immunoglobulin gene expression. J. Exp. Med. 179, 1585–1595 (1994).

    Article  CAS  Google Scholar 

  50. Herzenberg, L.A. & Kantor, A.B. B cell lineages exist in the mouse. Immunol. Today 14, 79–83 (1993).

    Article  CAS  Google Scholar 

  51. Fleming, S.D. et al. Mice deficient in complement receptors 1 and 2 lack a tissue injury-inducing subset of the natural antibody repertoire. J. Immunol. 169, 2126–2133 (2002).

    Article  CAS  Google Scholar 

  52. Reid, R.R. et al. Functional activity of natural antibody is altered in Cr2-deficient mice. J. Immunol. 169, 5433–5440 (2002).

    Article  CAS  Google Scholar 

  53. Janeway, C.A. Approaching the asymtote? Evolution and revolution in immunology. Cold Spring Harb. Symp. Quant. Biol. 54, 1–13 (1989).

    Article  CAS  Google Scholar 

  54. Pasare, C. & Medzhitov, R. Toll-like receptors: balancing host resistance with immune tolerance. Curr. Opin. Immunol. 15, 677–682 (2003).

    Article  CAS  Google Scholar 

  55. Fischer, M.B., Ma, M., Hsu, N. & Carroll, M.C. Local synthesis of C3 within the splenic lymphoid compartment can reconstitute the impaired immune response in C3-deficient mice. J. Immunol. 160, 2619–1625 (1998).

    CAS  PubMed  Google Scholar 

  56. DaCosta, X. et al. Humoral response to herpes simplex virus is complement dependent. Proc. Natl. Acad. Sci. USA 96, 12708–12712 (1999).

    Article  CAS  Google Scholar 

  57. Ochsenbien, A. et al. Protective T cell-independent antiviral antibody responses are dependent on complement. J. Exp. Med. 190, 1165–1174 (1999).

    Article  Google Scholar 

  58. Gustavsson, S., Kinoshita, T. & Heyman, B. Antibodies to murine complement receptor 1 and 2 can inhibit the antibody response in vivo without inhibiting T helper cell induction. J. Immunol. 154, 6524–6528 (1995).

    CAS  PubMed  Google Scholar 

  59. Kopf, M., Abel, B., Gallimore, A., Carroll, M. & Bachmann, M.F. Complement component C3 promotes T-cell priming and lung migration to control acute influenza virus infection. Nat. Med. 8, 373–378 (2002).

    Article  CAS  Google Scholar 

  60. Gerard, N.P. & Gerard, C. The chemotactic receptor for human C5a anaphylatoxin. Nature 349, 614–617 (1991).

    Article  CAS  Google Scholar 

  61. Ames, R.S. et al. Molecular cloning and characterization of the human anaphylatoxin C3a receptor. J. Biol. Chem. 271, 20231–20234 (1996).

    Article  CAS  Google Scholar 

  62. Kildsgaard, J. et al. Cutting edge: targeted disruption of the C3a receptor gene demonstrates a novel protective anti-inflammatory role for C3a in endotoxin-shock. J. Immunol. 165, 5406–5409 (2000).

    Article  CAS  Google Scholar 

  63. Baumgarth, N., Herman, O.C., Jager, G.C., Brown, L. & Herzenberg, L.A. Innate and acquired humoral immunities to influenza virus are mediated by distinct arms of the immune system. Proc. Natl. Acad. Sci. USA 96, 2250–2255 (1999).

    Article  CAS  Google Scholar 

  64. Stager, S. et al. Natural antibodies and complement are endogenous adjuvants for vaccine-induced CD8+ T-cell responses. Nat. Med. 9, 1287–1292 (2003).

    Article  Google Scholar 

  65. Campos, R.A. et al. Cutaneous immunization rapidly activates liver invariant Va14 NKT cells stimulating B-1 B cells to initiate T cell recruitment for elicitation of contact sensitivity. J. Exp. Med. 198, 1785–1796 (2003).

    Article  CAS  Google Scholar 

  66. Tsuji, R.F. et al. B cell-dependent T cell responses: IgM antibodies are required to elicit contact sensitivity. J. Exp. Med. 196, 1277–1290 (2002).

    Article  CAS  Google Scholar 

  67. Drouin, S.M., Corry, D.B., Kildsgaard, J. & Wetsel, R.A. Cutting edge: the absence of C3 demonstrates a role for complement in Th2 effector functions in a murine model of pulmonary allergy. J. Immunol. 167, 4141–4145 (2001).

    Article  CAS  Google Scholar 

  68. Drouin, S.M., Corry, D.B., Hollman, T.J., Kildsgaard, J. & Wetsel, R.A. Absence of the complement anaphylatoxin C3a receptor suppresses Th2 effector functions in a murine model of pulmonary allergy. J. Immunol. 169, 5926–5933 (2002).

    Article  CAS  Google Scholar 

  69. Hopken, U.E., Lu, B., Gerard, N.P. & Gerard, C. The C5a chemoattractant receptor mediates mucosal defence to infection. Nature 383, 86–89 (1996).

    Article  CAS  Google Scholar 

  70. Karp, C.L. et al. Identification of complement factor 5 as a susceptibility locus for experimental allergic asthma. Nat. Immunol. 1, 221–226 (2000).

    Article  CAS  Google Scholar 

  71. Wittmann, M. et al. C5a suppresses the production of IL-12 by IFN-gamma-primed and lipopolysaccharide-challenged human monocytes. J. Immunol. 162, 6763–6769 (1999).

    CAS  PubMed  Google Scholar 

  72. Karp, C.L. et al. Mechanism of suppression of cell-mediated immunity by measles virus. Science. 273, 228–231 (1996).

    Article  CAS  Google Scholar 

  73. Kemper, C. et al. Activation of human CD4+ cells with CD3 and CD46 induces a T-regulatory cell 1 phenotype. Nature 421, 388–392 (2003).

    Article  CAS  Google Scholar 

  74. Colten, H.R. & Dowton, S.B. Regulation of complement gene expression. Biochem. Soc. Symp. 51, 37–46 (1986).

    CAS  PubMed  Google Scholar 

  75. Petry, F., Botto, M., Holtappels, R., Walport, M.J. & Loos, M. Reconstitution of the complement function in C1q-deficient (C1qa-/) mice with wild-type bone marrow cells. J. Immunol. 167, 4033–4037 (2001).

    Article  CAS  Google Scholar 

  76. Schwaeble, W. et al. Follicular dendritic cells, interdigitating cells, and cells of the monocyte-macrophage lineage are the C1q-producing sources in the spleen. Identification of specific cell types by in situ hybridization and immunohistochemical analysis. J. Immunol. 155, 4971–4978 (1995).

    CAS  PubMed  Google Scholar 

  77. Gadjeva, M. et al. Macrophage-derived complement component C4 can restore humoral immunity in C4-deficient mice. J. Immunol. 169, 5489–5495 (2002).

    Article  CAS  Google Scholar 

  78. Verschoor, A., Brockman, M.A., Knipe, D.M. & Carroll, M.C. Cutting edge: myeloid complement C3 enhances the humoral response to peripheral viral infection. J. Immunol. 167, 2446–2451 (2001).

    Article  CAS  Google Scholar 

  79. Verschoor, A., Brockman, M.A., Gadjeva, M., Knipe, D.M. & Carroll, M.C. Myeloid C3 determines induction of humoral responses to peripheral herpes simplex virus infection. J. Immunol. 171, 5363–5371 (2003).

    Article  CAS  Google Scholar 

  80. Guinamard, R., Okigaki, M., Schlessinger, J. & Ravetch, J.V. Absence of marginal zone B cells in Pyk-2-deficient mice defines their role in the humoral response. Nat. Immunol. 1, 31–36 (2000).

    Article  CAS  Google Scholar 

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Acknowledgements

I thank R. Barrington for review of the manuscript, and current and past members of the laboratory for their contributions to the understanding of how complement influences adaptive immunity. The related work from my laboratory is supported by grants from the National Institutes of Health (AI39246-09, AI36389-08, AI52343-03 and AI53570-02).

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    Michael C Carroll

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Carroll, M. The complement system in regulation of adaptive immunity. Nat Immunol 5, 981–986 (2004). https://doi.org/10.1038/ni1113

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