Regulation of B cell survival in xid mice by the proto-oncogene bcl-2

CBA/N mice carry an X-linked immunodeficiency (rid) due to a point mutation in the Bruton's tyrosine kinase (btk) gene, rid mice have a smaller peripheral B cell pool than normal animals, lack CD5(+) B cells (B1), and are hyporesponsive to mitogenic anti-Igs and thymus-independent type 2 Ags, The proto-oncogene bcl-2 affects B cell homeostasis by suppressing programmed cell death, We hypothesized that reduced bcl-2 expression could enhance programmed cell death in rid B cells, directly causing poor peripheral B cell survival and indirectly affecting Ag responsiveness, We measured and compared levels of endogenous Bcl-2 protein and spontaneous apoptosis in rid and normal B cells, and determined the effect of a human bcl-2/Ig minigene on B cell survival and Ag responsiveness in bcl-2 transgenics, The amount of endogenous Bcl-2 was reduced fivefold in freshly isolated rid B cells compared with that in normal cells, but was equal in rid and normal T cells. Attrition by spontaneous apoptosis was significantly higher in cultured rid B cells. Expression of the bcl-2 transgene suppressed apoptosis equally in normal and rid B cells, prolonged in vitro survival, and markedly expanded in vivo the follicular B cell population normally reduced in rid mice, However, most rid defects persisted; xid/bcl-2 mice remained deficient in B1 cells and hyporesponsive to anti-Igs, thymus-independent type 1 Ags, and thymus-independent type 2 Ags. The data suggest that signal transduction pathways using Btk independently regulate B cell survival and Ag responsiveness.