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.
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17 August 1998
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August 17 1998
Repression of B7.2 on Self-reactive B Cells Is Essential to Prevent Proliferation and Allow Fas-mediated Deletion by CD4+ T Cells
Jeffrey C. Rathmell,
Jeffrey C. Rathmell
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
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Sylvie Fournier,
Sylvie Fournier
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
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Bennett C. Weintraub,
Bennett C. Weintraub
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
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James P. Allison,
James P. Allison
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
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Christopher C. Goodnow
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
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Jeffrey C. Rathmell
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
Sylvie Fournier
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
Bennett C. Weintraub
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
James P. Allison
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
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
Address correspondence to Christopher C. Goodnow, Medical Genome Centre, Division of Molecular Medicine, John Curtin School of Medical Research, Mills Rd., P.O. Box 334, Canberra, ACT 2601, Australia. Phone: 61-2-6249-3621; Fax: 61-2-6279-8512; E-mail: [email protected]
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.
Received:
February 02 1998
Revision Received:
May 26 1998
Online ISSN: 1540-9538
Print ISSN: 0022-1007
1998
J Exp Med (1998) 188 (4): 651–659.
Article history
Received:
February 02 1998
Revision Received:
May 26 1998
Citation
Jeffrey C. Rathmell, Sylvie Fournier, Bennett C. Weintraub, James P. Allison, Christopher C. Goodnow; Repression of B7.2 on Self-reactive B Cells Is Essential to Prevent Proliferation and Allow Fas-mediated Deletion by CD4+ T Cells . J Exp Med 17 August 1998; 188 (4): 651–659. doi: https://doi.org/10.1084/jem.188.4.651
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