1. Laboratory of Lymphocyte Signaling, The Rockefeller University, New York, New York 10021, USA
2. Biogen Idec, Inc., Cambridge, Massachusetts 02142, USA
3. Max Planck Institute for Experimental Endocrinology, D 30625 Hannover, Germany
4. Garvan Institute of Medical Research, St Vincent Hospital, Darlinghurst, NSW 2010, Sydney, Australia

Correspondence to: Alexander Tarakhovsky¹ Email: tarakho@mail.rockefeller.edu

Abstract

Approximately 65% of B cells generated in human bone marrow are potentially harmful autoreactive B cells¹. 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, 3, 4, 5}. Escape of self-reactive B cells from tolerance permits production of pathogenic auto-antibodies⁶; recent studies suggest that extended B lymphocyte survival is a cause of autoimmune disease in mice and humans⁷. Here we report a mechanism for the regulation of peripheral B-cell survival by serine/threonine protein kinase C (PKC): spontaneous death of resting B cells is regulated by nuclear localization of PKC 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 PKC. Our data suggest the existence of a previously unknown BAFF-induced and PKC-mediated nuclear signalling pathway which regulates B-cell survival.

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