REPRESSION OF B7.2 ON SELF-REACTIVE B-CELLS IS ESSENTIAL TO PREVENT PROLIFERATION AND ALLOW FAS-MEDIATED DELETION BY CD4(-CELLS() T)

Peripheral tolerance mechanisms normally prevent delivery of T cell. h elp to anergic self-reactive B cells that accumulate in the T zones of spleen and lymph nodes. Chronic exposure to self-antigens desensitize s B cell antigen receptor (BCR) signaling on anergic B cells so that t hey are not stimulated into clonal expansion by CD4(+) T cells but ins tead are eliminated by Fas (CD95)-induced apoptosis, Because a range o f BCR-induced signals and responses are repressed in anergic B cells, it is not known which of these are critical to regulate for Fas-mediat ed 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 sh ow here that restoring B7.2 expression on tolerant B cells using a con stitutively expressed B7.2 transgene is sufficient to prevent Fas-medi ated deletion and to trigger extensive T cell-dependent clonal expansi on and autoantibody secretion in the presence of specific T cells. Dys regulated expression of B7.2 on tolerant B cells caused a more extreme reversal of peripheral tolerance than that caused by defects in Fas o r Fas ligand, and resulted in T cell-dependent clonal expansion and an tibody secretion comparable in magnitude to that made by foreign antig en-specific B cells. These findings demonstrate that repression of B7. 2 is critical to eliminate autoreactive B cells by Fas in B cell-T cel l interactions, The possible role of B7.2 dysregulation in systemic au toimmune diseases is discussed.