A novel cDNA clone termed R2 was isolated by subtractive hybridization of a cDNA library of phytohemagglutinin (PHA)/phorbol myristate acetate-stimulated Jurkat cells and by rescreening a cDNA library of PHA-stimulated peripheral blood lymphocytes. It hybridizes to a single mRNA species of about 2.2 kb, which is inducible in lymphoid cells and codes for a protein of 267 amino acids which contains four potential transmembrane domains. A computer-aided comparison showed strong homology to four other membrane proteins, the pan B cell marker CD37, the pan leukocyte marker CD53, the melanoma antigen ME491 and surprisingly, the Schistosoma mansoni antigen Sm23. The four human proteins share a number of additional similarities in their overall structure. These include identical spacing of the transmembrane domains, similar hydro-phobicity plots, possible N-linked glycosylation sites of similar number and position as well as similar distribution of the cysteine residues. The majority of these characteristics are still conserved in the evolutionary most distant member of this family, the Schistosoma mansoni antigen Sm23. Here we introduce this new protein superfamily and characterize the inducible, lymphoid-specific member R2.