A novel monoclonal antibody (mAb) was established in an attempt to look for a cell-surface molecule that delivered a signal regulating apoptotic cell death of B cells. Because spleen cells in resting culture die from apoptosis, mAb were looked for that were able to prolong spleen cell survival in vitro. This screening selected mAb CS/2. CS/2 not only prolonged spleen cell survival in vitro, but also protected spleen cells from apoptotic cell death brought about by irradiation or dexamethasone. Moreover, stimulation of spleen cells with CS/2 mAb induced changes of cells to blastoid morphology, and a significant uptake of [3H]thymidine ([3H]TdR). The antigen recognized by CS/2 mAb (CS/2 Ag) was expressed on preB cells, B cells, and Mac-1+ cells. The cells surviving in vitro culture or irradiation in response to ligation with CS/2 mAb were mostly B cells expressing the CS/2 Ag. In addition, B cells from X-linked immunodeficient (XID) mice did not respond to CS/2 mAb. These results indicate that CS/2 mAb is agonistic to B cells, and that XID mice are deficient in this CS/2 mAb-mediated activation pathway. Determination of the amino-terminal 24 amino acid residues revealed that the CS/2 Ag appears to be identical to the CS/2 mAb is directed against a murine CD38 homologue, and suggest a possible role of the murine CD38 homologue in controlling apoptotic cell death of B cells.