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J. Exp. Med.,
Volume 188, Number 4, August 17, 1998 651-659
By
From the * Howard Hughes Medical Institute and the Department of Microbiology and Immunology,
Stanford University, Stanford, California 94305; the Peripheral tolerance mechanisms normally prevent delivery of T cell help to anergic self-reactive B cells that accumulate in the T zones of spleen and lymph nodes. Chronic exposure to self-antigens desensitizes B cell antigen receptor (BCR) signaling on anergic B cells so that they
are not stimulated into clonal expansion by CD4+ T cells but instead are eliminated by Fas
(CD95)-induced apoptosis. Because a range of BCR-induced signals and responses are repressed in anergic B cells, it is not known which of these are critical to regulate for Fas-mediated peripheral tolerance. Display of the costimulatory molecule, B7.2 (CD86), represents a
potentially important early response to acute BCR engagement that is poorly induced by antigen on anergic B cells. We show here that restoring B7.2 expression on tolerant B cells using a
constitutively expressed B7.2 transgene is sufficient to prevent Fas-mediated deletion and to
trigger extensive T cell-dependent clonal expansion and autoantibody secretion in the presence of specific T cells. Dysregulated expression of B7.2 on tolerant B cells caused a more extreme reversal of peripheral tolerance than that caused by defects in Fas or Fas ligand, and resulted in T cell-dependent clonal expansion and antibody secretion comparable in magnitude
to that made by foreign antigen-specific B cells. These findings demonstrate that repression of
B7.2 is critical to eliminate autoreactive B cells by Fas in B cell-T cell interactions. The possible role of B7.2 dysregulation in systemic autoimmune diseases is discussed.
Australian Cancer Research Foundation
Genetics Laboratory and Medical Genome Centre, John Curtin School of Medical Research,
Australian National University, Canberra, ACT 2601, Australia; and the § Department of Molecular
and Cellular Biology and the Cancer Research Laboratory, University of California at Berkeley,
Berkeley, California 94720
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