Roles of membrane domains in the signaling pathway for B cell survival

B cell response to antigens forms the basis for humoral immune responses. Mature B cells are rescued from spontaneous apoptosis in the presence of survival factors such as anti-IgM antibody, LPS, and anti-CD40 antibody. This in vitro rescue correlates with in vivo B-cell proliferation and differentiation induced by thymus-independent (TI) -2, TI-1, and thymus-dependent (TD) antigens. Crosslinking of B cell receptor (BCR) by anti-IgM antibody promotes a positive feedback loop in the vicinity of BCR to activate those tyrosine kinases, Syk and Btk, crucial for the NF-γB activation. Ligation of CD40 triggers a recruitment of IγB kinase through TNF receptor-activated factors (TRAFs). Sphingolipid- and cholesterol-enriched membrane domains are important for the assembly of the signaling molecules during TI-2 and TD antigens recognition. B cells can be rescued from apoptosis even in the absence of antigen by an agonistic antibody (anti-CD38 antibody), CS/2. An absolute requirement of Syk and Btk in the CS/2 action suggests that an intracellular signaling pathway of CS/2 is similar to that induced by BCR-crosslinking. However, the action of CS/2 does not elicit appreciable tyrosine phosphorylation. Our data implies that CS/2 induces a conformational change of CD38 within the membrane domains, which leads to a generation of sphingolipid-mediated B cell survival signal.