Regulation of B-cell survival by BAFF-dependent PKCδ-mediated nuclear signalling

Approximately 65% of B cells generated in human bone marrow are potentially harmful autoreactive B cells(1). Most of these cells are clonally deleted in the bone marrow, while those autoreactive B cells that escape to the periphery are anergized or perish before becoming mature B cells(2-5). Escape of self-reactive B cells from tolerance permits production of pathogenic auto-antibodies(6); recent studies suggest that extended B lymphocyte survival is a cause of autoimmune disease in mice and humans(7). Here we report a mechanism for the regulation of peripheral B-cell survival by serine/threonine protein kinase Cdelta (PKCdelta): spontaneous death of resting B cells is regulated by nuclear localization of PKCdelta that contributes to phosphorylation of histone H2B at serine 14 (S14-H2B). We show that treatment of B cells with the potent B-cell survival factor BAFF ('B-cell-activating factor belonging to the TNF family') prevents nuclear accumulation of PKCdelta. Our data suggest the existence of a previously unknown BAFF-induced and PKCdelta-mediated nuclear signalling pathway which regulates B-cell survival.