¹ Immunology Program, Howard Hughes Medical Institute and Department of Microbiology and Immunology, Stanford University, Stanford, California, USA

Correspondence: CC Goodnow, Medical Genome Centre and Australian Cancer Research Foundation Genetics Laboratory, John Curtin School of Medical Research, Australian National University, Mills Road, PO Box 334, Canberra, ACT 2601, Australia

Received 3 February 1998; Accepted 21 May 1998.

Abstract

The expression of CD95 (Fas/APO-1) on B cells has been shown to play a direct role in their fate. B␣cells that chronically bind antigen due to prolonged antigen exposure, such as self-reactive B cells, are induced to express CD95 by CD40 ligand (CD40L) and are subsequently eliminated by CD95 ligand (CD95L) when they present antigen to CD4⁺ T cells. B cells that bind antigen acutely due to sudden antigen encounter, such as foreign antigen reactive B cells, up-regulate CD95, but are normally protected from CD95L-mediated apoptosis. Here, however, it is shown in vivo that foreign antigen-specific B cells fail to be protected from CD95-dependent elimination in a host that is CD95 deficient, regardless of antigenic challenge. These data indicate that B cell antigen receptor (BCR)-induced protection against CD95L-mediated apoptosis is not absolute but depends upon other micro-environmental factors in vivo. The normal balance between T cell-dependent humoral immunity and tolerance is thus regulated intrinsically by CD95 expression on responding B cells, and extrinsically by CD95-mediated control of CD95L or other molecules in the lymphoid micro-environment.