Complement receptor type 2 (CR2), also known as complement C3d receptor, Epstein-Barr virus receptor, and CD21 (cluster of differentiation 21), is a protein that in humans is encoded by the CR2 gene.
CR2 is involved in the complement system. It binds to iC3b (inactive derivative of C3b), C3dg, or C3d.B cells have CR2 receptors on their surfaces, allowing the complement system to play a role in B-cell activation and maturation 
CR2 on mature B cells form a complex with two other membrane proteins, CD19 and CD81(=TAPA-1). The CR2-CD19-CD81 complex is often called the B cell coreceptor complex, because CR2 binds to antigens through attached C3d (or iC3b or C3dg) when the membrane IgM binds to the antigen. This results in the B cell having greatly enhanced response to the antigen.
The canonical Cr2/CD21 gene of subprimate mammals produces two types of complement receptor (CR1, ca. 200 kDa; CR2, ca. 145 kDa) via alternative mRNA splicing. The murine Cr2 gene contains 25 exons; a common first exon is spliced to exon 2 and to exon 9 in transcripts encoding CR1 and CR2, respectively. A transcript with an open reading frame of 4,224 nucleotides encodes the long isoform, CR1; this is predicted to be a protein of 1,408 amino acids that includes 21 short consensus repeats (SCR) of ca. 60 amino acids each, plus transmembrane and cytoplasmic regions. Isoform CR2 (1,032 amino acids) is encoded by a shorter transcript (3,096 coding nucleotides) that lacks exons 2-8 encoding SCR1-6. CR1 and CR2 on murine B cells form complexes with a co-accessory activation complex containing CD19, CD81, and the fragilis/Ifitm (murine equivalents of LEU13) proteins.
The CR2 gene of primates produces only the smaller isoform, CR2; primate complement receptor 1, which recapitulates many of the structural domains and presumed functions of Cr2-derived CR1 in subprimates, is encoded by a distinct CR1 gene (apparently derived from the gene Crry of subprimates).
Isoforms CR1 and CR2 derived from the non-primate Cr2 locus possess the same C-terminal sequence, such that association with and activation through CD19 should be equivalent. CR1 can bind to C4b and C3b complexes, whereas CR2 (murine and human) binds to C3dg-bound complexes. CR1, a surface protein produced primarily by follicular dendritic cells, appears to be critical for generation of appropriately activated B cells of the germinal centre and for mature antibody responses to bacterial infection.
Although CR2 is present on all mature B-cells and follicular dendritic cells (FDCs), this becomes readily apparent only when immunohistochemistry is performed on frozen sections. In more conventional paraffin-embedded tissue samples, only the FDCs retain the staining pattern. As a result, CR2, more commonly called CD21 in the context of immunohistochemistry, can be used to demonstrate the FDC meshwork in lymphoid tissue.
^ abFrank K, Atkinson JP (2001). "Complement system." In Austen KF, Frank K, Atkinson JP, Cantor H. eds. Samter's Immunologic Diseases, 6th ed. Vol. 1, p. 281-298, Philadelphia: Lippincott Williams & Wilkins, ISBN 0-7817-2120-2.
^Abbas AK, Lichtman AH (2003). Cellular and Molecular Immunology, 5th ed. Philadelphia: Saunders, ISBN 0-7216-0008-5
^Bradbury LE, Kansas GS, Levy S, Evans RL, Tedder TF (November 1992). "The CD19/CD21 signal transducing complex of human B lymphocytes includes the target of antiproliferative antibody-1 and Leu-13 molecules". J. Immunol.149 (9): 2841–50. PMID1383329.
^Horváth G, Serru V, Clay D, Billard M, Boucheix C, Rubinstein E (November 1998). "CD19 is linked to the integrin-associated tetraspans CD9, CD81, and CD82". J. Biol. Chem.273 (46): 30537–43. doi:10.1074/jbc.273.46.30537. PMID9804823.
^Yefenof E, Klein G, Jondal M, Oldstone MB (June 1976). "Surface markers on human B and T-lymphocytes. IX. Two-color immunofluorescence studies on the association between ebv receptors and complement receptors on the surface of lymphoid cell lines". Int. J. Cancer17 (6): 693–700. doi:10.1002/ijc.2910170602. PMID181330.
Gauffre A, Viron A, Barel M et al. (1992). "Nuclear localization of the Epstein-Barr virus/C3d receptor (CR2) in the human Burkitt B lymphoma cell, Raji.". Mol. Immunol.29 (9): 1113–20. doi:10.1016/0161-5890(92)90044-X. PMID1323059.
Kalli KR, Ahearn JM, Fearon DT (1991). "Interaction of iC3b with recombinant isotypic and chimeric forms of CR2.". J. Immunol.147 (2): 590–4. PMID1830068.
Barel M, Gauffre A, Lyamani F et al. (1991). "Intracellular interaction of EBV/C3d receptor (CR2) with p68, a calcium-binding protein present in normal but not in transformed B lymphocytes.". J. Immunol.147 (4): 1286–91. PMID1831222.
Kurtz CB, Paul MS, Aegerter M et al. (1989). "Murine complement receptor gene family. II. Identification and characterization of the murine homolog (Cr2) to human CR2 and its molecular linkage to Crry.". J. Immunol.143 (6): 2058–67. PMID2528587.
Fujisaku A, Harley JB, Frank MB et al. (1989). "Genomic organization and polymorphisms of the human C3d/Epstein-Barr virus receptor.". J. Biol. Chem.264 (4): 2118–25. PMID2563370.
Barel M, Balbo M, Gauffre A, Frade R (1995). "Binding sites of the Epstein-Barr virus and C3d receptor (CR2, CD21) for its three intracellular ligands, the p53 anti-oncoprotein, the p68 calcium binding protein and the nuclear p120 ribonucleoprotein.". Mol. Immunol.32 (6): 389–97. doi:10.1016/0161-5890(95)00005-Y. PMID7753047.