Human complement receptor type 2 (CR2) is the B-lymphocyte receptor both for the C3d fragment of the third component of complement and for the Epstein-Barr virus. Amino acid sequence analysis of tryptic peptides of CR2 revealed a strong degree of homology with the human C3b/C4b receptor, CR1. This homology suggested that CR1 gene sequences could be used to detect the CR2 sequences at conditions of low-stringency hybridization. Upon screening a human tonsillar cDNA library with CR1 cDNA sequences, two clones were identified that hybridized at low, but not at high, stringency. Redundant oligonucleotides specific for CR2 sequences were synthesized and used to establish that the two cDNA clones weakly hybridizing with the CR1 cDNA contained CR2 sequences. One of these CR2 cDNA clones hybridized to oligonucleotides derived from two distinct CR2 tryptic peptides, whereas the other, smaller cDNA clone hybridized to oligonucleotides derived from only one of the CR2 peptides. Nucleotide sequence analysis of the CR2 cDNA confirmed that the site of oligonucleotide hybridization was identical to that predicted from the peptide sequence, including flanking sequences not included within the oligonucleotide probes. The CR2-specific cDNA sequences identified a poly(A)+ RNA species of 5 kilobases in RNA extracted from human B cells but did not hybridize to any RNA obtained from the CR2-negative T-cell line HSB-2, thus confirming the appropriate size and tissue-specific distribution for the CR2 mRNA. The striking peptide sequence homology between CR2 and CR1 and the cross-hybridization of the CR2 cDNA with the CR1-specific sequences allow the placement of CR2 in a recently defmed gene family of C3-and C4-binding proteins consisting of CR1, C4-binding protein, factor H, and now, CR2.The C3d/Epstein-Barr virus (EBV) receptor (complement receptor type 2, CR2) of human B lymphocytes is a Mr 145,000 glycoprotein (1-3) comprised of a single polypeptide of Mr 110,000 and 8-11 N-linked oligosaccharides (4). It is expressed by B lymphocytes (5, 6) and follicular dendritic cells of the spleen (7). CR2 recognizes the d region of the C3 component of complement (5, 6) and also serves as the membrane receptor for the human herpesvirus EBV (8, 9), which induces polyclonal activation and immortalization of B lymphocytes and is associated with Burkitt lymphoma and nasopharyngeal carcinoma. CR2 may have a role in physiologic B-cell activation (10, 11) and is phosphorylated when B cells are treated with phorbol 12-myristate 13-acetate or antibody to surface immunoglobulin (12).The recent purification of CR2 permitted the demonstration (13) of significant similarities between its amino acid composition and that of three other proteins of the complement system: factor H, C4-binding protein, and the C3b receptor (complement receptor type 1, CR1). Factor H and C4-binding protein are plasma proteins and CR1 is a membrane glycoprotein found on erythrocytes, most leukocytes, and glomerular podocytes (14). These proteins share certain functions, s...