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Jeffrey C. Rathmell^*, Sylvie Fournier, Bennett C. Weintraub^*,, James P. Allison, and Christopher C. Goodnow^*,

From the ^* Howard Hughes Medical Institute and the Department of Microbiology and Immunology, Stanford University, Stanford, California 94305; the 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

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.

Key Words: B7.2 (CD86) • Fas (CD95) • B cell antigen receptor • B cell • autoimmunity

J.C. Rathmell's current address is Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, 924 E. 57th St., R402, Chicago, IL 60637.

Abbreviations used: BCR, B cell antigen receptor; CTLA4, cytotoxic lymphocyte–associated antigen 4; HEL, hen egg lysozyme; HPRT, hypoxanthine phosphoribosyltransferase; L, ligand; PI, propidium iodide; RT, reverse transcription; tg, transgenic.

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