Complement receptor 2 (CR2/CD21)

Rozaleen Dash, Nibhriti Das


Human complement receptor type 2 (CR2/CD21) is a surface-associated glycoprotein which binds to a variety of endogenous ligands, including the complement component C3 fragments iC3b, C3dg and C3d, the low-affinity IgE receptor CD23, and the type I cytokine, interferon-alpha. This receptor serves as an important interface between the complement system and adaptive immunity. It is expressed on B-lymphocytes, follicular dendritic cells, some epithelial cells, peripheral blood T cells. CR2 also play an important role in enhancing humoral immunity to T-dependent and T-independent foreign antigens and in regulating T-cell immunity to self and non-self-antigens. It is an important receptor that amplifies B lymphocyte activation by bridging the innate and adaptive immune systems. CR2 ligands include complement C3d and Epstein-Barr virus glycoprotein 350/220. Regions of EBV have structural similarity to C3dg, which allows it to bind CR2, and thereby gain access to cell’s interior. It also acts as receptor for other components or activators of innate immunity such as IFN-α, an anti-viral cytokine and DNA-DNA containing complexes such as chromatin. The binding of CR2 to IFN-α is speculated to cause B cell activation but their roles are still not clear. Variations or deletions of the CR2 gene in humans, or the Cr2 gene in mice associate with a variety of autoimmune and inflammatory conditions.


Autoimmunity, B cell signalling, Complement receptor 2 (CR2/CD21), Regulators of complement activation

Full Text:



Ahearn JM, Fearon DT. Structure and function of the C receptors, CR1 (CD35) and CR2 (CD21). Adv. Immunol. 1989; 46: 183 - 219.

Delibrias CC, Fischer E, Bismuth G, Kazatchkine MD. Expression, molecular association, and functions of C3 complement receptors CR1 (CD35) and CR2 (CD21) on the human T cell line HPB-ALL. J Immunol. 1992;149:768-74.

Carter RH, Spycher MO, Ng YC, Hoffman R, Fearon DT. Synergistic interaction between complement receptor type 2 and membrane IgM on B lymphocytes. J Immunol. 1988;141:457-63.

Fischer E, Delibrias C, Kazatchkine MD. Expression of CR2 (the C dg/EBV receptor, CD21) on normal human peripheral blood T lymphocytes. J Immunol. 1991;141(6):865-69.

Iida K, Nadler L, Nussenzweig V. Identification of the membrane receptor for the complement fragment C3d by means of a monoclonal antibody. J Exp Med. 1983;158:1021-33.

Weis JJ, Tedder TF, Fearon DT. Identification of a 145,000 Mr membrane protein as the C3d receptor (CR2) of human B lymphocytes. Proc Natl Acad Sci USA. 1984;81:881-5.

Tedder TF, Clement LT, Cooper MD. Expression of C3d receptors during human B cell differentiation: immunofluorescence analysis with the HB-5 monoclonal antibody. J Immunol. 1984;133:678-83.

Larcher C, Schulz TF, Hofbauer J, Hengster P, Romani N, Wachter H, Dierich MP. Expression of the C3d/EBV receptor and of other cell membrane surface markers is altered upon HIV-1 infection of myeloid, T, and B cells. J Acquir Immune Defic Syndr. 1990;3:103-8.

Delibrias CC, Fischer E, Bismuth G, Kazatchkine MD. Expression, molecular association, and functions of C3 complement receptors CR1 (CD35) and CR2 (CD21) on the human T cell line HPB-ALL. J Immunol. 1992;149:768-74.

Carroll MC, Prodeus AP. Linkages of innate and adaptive immunity. Curr Opin Immunol. 1998;10:36-40.

Moir SA, Malaspina Y, Chun TW, Lowe T, Adelsberger J, Baseler M, et al. B cells of HIV 1 infected patients bind virions through CD21- complement interaction and transmit infectious viruses to activated T cells. J Exp Med. 2000;192:637-46.

Fischer EM, Mouhoub A, Maillet F, Fremeaux-Bacchi V, Krief C, GouldH, et al. Expression of CD21 is developmentally regulated during thymic maturation of human T lymphocytes. Int Immunol. 1999;11:1841-9.

Nemerow GR, McNaughton ME, Cooper NR. Monoclonal antibody to the Epstein-Barr virus receptor induces human B lymphocyte activation and differentiation. Trans Assoc Am Physicians. 1985;98:290-300.

Fingeroth JD, Heath ME, Ambrosino DM. Proliferation of resting B cells is modulated by CR2 and CR1. Immunol Lett. 1989;21:291-301.

Dempse PW, Allison ME, Akkaraju S, Goodnow CC, Fearon DT. C3d of complement as a molecular adjuvant: bridging innate and acquired immunity. Science. 1996;271:348-50.

Cherukuri A, Cheng PC, Pierce SK. The role of the CD19/CD21 complex in B cell processing and presentation of complement-tagged antigens. J Immunol. 2001a;167:163-72.

Mongini PK, Inman JK. Cytokine dependency of human B cell cycle progression elicited by ligands which coengage BCR and the CD21/CD19/CD81 costimulatory complex. Cell Immunol. 2001;207:127-40.

Roberts T, Snow EC. Cutting edge: recruitment of the CD19/CD21 coreceptor to B cell antigen receptor is required for antigen-mediated expression of Bcl-2 by resting and cycling hen egg lysozyme transgenic B cells. J Immunol. 1999;162:4377-80.

Lanzavecchia A, Abrignani S, Scheidegger D, Obrist R, Dorken B, Moldenhauer G. Antibodies as antigens. The use of mouse monoclonal antibodies to focus human T cells against selected targets. J Exp Med. 1988;167:345-52.

Ahearn JM, Fischer MB, Croix D, Goerg S, Ma M, Xia 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. 1996;4:251-62.

Schwab J, Illges H. Regulation of CD21 expression by DNA methylation and histone deacetylation. IntImmunol. 2001a;13:705-10.

Schwab J, Illges H. Silencing of CD21 expression in synovial lymphocytes is independent of methylation of the CD21 promoter CpG island. Rheumatol Int. 2001b;20:133-7.

Croix DA, Ahearn JM, Rosengard AM, Han S, Kelsoe G, Ma M, et al. Antibody response to a T-dependent antigen requires B cell expression of complement receptors. J Exp Med. 1996;183:1857-64.

Myones BL, Ross GD. Identification of a spontaneously shed fragment of B cell complement receptor type two (CR2) containing the C3d-binding site. Complement. 1987;4:87-98.

Ling N, Hansel T, Richardson P and Brown B. Cellular origins of serum complement receptor type 2 in normal individuals and in hypogamma globulinaemia. Clin Exp Immunol. 1991;84:16-22.

Fremeaux-Bacchi V, Fischer E, Lecoanet-Henchoz S, Mani JC, Bonnefoy JY, Kazatchkine MD. Soluble CD21 (sCD21) forms biologically active complexes with CD23: sCD21 is present in normal plasma as a complex with trimeric CD23 and inhibits soluble CD23-induced IgE synthesis by B cells. Int. Immunol. 1998b;10:1459-66.

Guthridge JM, Young K, Gipson MG, Sarrias MR, Szakonyi G, Chen XS, et al. Epitope mapping using the x-ray crystallographic structure of complement receptor type 2 (CR2)/CD21: identification of a highly inhibitory monoclonal antibody that directly recognizes the CR2-C3d interface1. Journal Immunol. 2001;167:5758-66.

Masilamani M, Nowack R, Witte T, Schlesier M, Warnatz K, Glocker MO, et al. Reduction of soluble complement receptor 2/CD21 in systemic lupus erythomatosus and Sjogren's syndrome but not juvenile arthritis. Scand J Immunol. 2004;60:625-30.

Larcher C, Kempkes B, Kremmer E, Prodinger WM, Pawlita M, Bornkamm GW, et al. Expression of Epstein-Barr virus nuclear antigen-2 (EBNA2) induces CD21/CR2 on B and T cell lines and shedding of soluble CD21. Eur J Immunol. 1995;25:1713-9.

Grattone ML, Villiers CL, Villier MB, Drouet C, Marche PN. Co-operation between human CR1 (CD35) and CR2 (CD21) in internalization of their C3b and iC3b ligands by murine transfected fibroblasts. Immunology. 1999;98:152-7.

Illges H, Braun M, Peter HH, Melchers I. Reduced expression of the complement receptor type 2 (CR2, CD21) by synovial fluid B and T lymphocytes. Clin Exp Immunol. 2000;122:270-6.

Wilson JG, Ratnoff WD, Schur PH, Fearson DT. Decreased expression of the C3b/C4b receptor (CR1) and the C3d receptor (CR2) on B lymphocytes and CR1 on neutrophils of patients with systemic lupus erythematosus. Arthritis Rheum. 1986;29:739-47.

Young KA, Chen XS, Holens V, Hannrn JP. Isolating the Epstein- Barr virus gp 350 /220 binding site on complement receptor type 2 (CR2/CD21). J Biol Chem. 2007;282(50):36614-25.

Prodeus AP, Goerg S, Shen LM, Pozdnyakova OO, Chu L, Alicot EM, et al. A critical role for complement in maintenance of self-tolerance. Immunity. 1998;9:721-31.

Gorelik L, Cutler AH, Thill G, Miklasz SD, Shea DE, Ambrose C, Bixler SA, Su L, Scott ML, Kalled SL. Cutting edge: BAFF regulates CD21/35 and CD23 expression independent of its B cell survival function. J Immunol. 2004;172:762-6.

Pers JO, Daridon C, Devauchelle V, Jousse S, Saraux A, Jamin C, Youinou P, Stohl W. BAFF overexpression is associated with autoantibody production in autoimmune diseases. Ann New York Acad Sci. 2005;1050(1),34-9.

Marquart HV, Svendsen A, Rasmussen JM, Nielsen CH, Junker P, Svehag SE, Leslie RG. Complement receptor expression and activation of the complement cascade on B lymphocytes from patients with systemic lupus erythematosus (SLE). Clin Exp Immunol. 1995;101:60-5.

Douglas KB, Windels DC, Zhao J. Complement receptor 2 polymorphisms associated with systemic lupus erythematosus modulate alternative splicing. Genes Immun. 2009;10(5):457-69.