The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1999/1/435/ $5.00
The Journal of Experimental Medicine, Volume 189, Number 2, January 18, 1999 435-440

Brief Definitive Reports

B7-1 or B7-2 Is Required to Produce the Lymphoproliferative Phenotype in Mice Lacking Cytotoxic T Lymphocyte–associated Antigen 4 (CTLA-4)

Didier A. Mandelbrot*,{ddagger}, Alexander J. McAdam*, and Arlene H. Sharpe*

From the * Immunology Research Division, Department of Pathology, and {ddagger} Renal Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115

The costimulatory molecules B7-1 and B7-2 regulate T lymphocyte activation by delivering activating signals through CD28 and inhibitory signals through cytotoxic T lymphocyte–associated antigen 4 (CTLA-4). The importance of CTLA-4–mediated inhibition was demonstrated by the uncontrolled T cell activation and lymphoproliferative disease that develops in CTLA-4–deficient (–/–) mice. To examine the role of B7 signaling in the activation of CTLA-4–deficient T cells, we bred CTLA-4–/– mice with mice lacking B7-1, B7-2, or both B7 molecules. The CTLA-4/B7-1–/– and the CTLA-4/B7-2–/– mice develop lymphoproliferation and enhanced T cell activation. Mice lacking CTLA-4, B7-1, and B7-2 have a normal life-span, and do not have lymphocytic infiltrates in any organs, or increased T cell activation. Therefore, the two B7 molecules have overlapping functions, since either B7-1 or B7-2 alone can cause the CTLA-4–/– phenotype. Elimination of both B7-1 and B7-2 from the CTLA-4– deficient mouse abrogates the lymphocyte activation and disease, and does not reveal evidence for additional stimulatory CD28 ligands. The CTLA-4–/– phenotype can be reproduced with anti-CD28 antibody in mice lacking CTLA-4, B7-1, and B7-2, but wild-type mice are unaffected by the same treatment. This suggests that the inhibitory function of CTLA-4 can overcome strong CD28-mediated signaling in vivo.

Key Words: cytotoxic T lymphocyte–associated antigen 4 • B7 • knockout mouse • costimulation • T lymphocyte

Address correspondence to Didier A. Mandelbrot, 221 Longwood Ave., LMRC Rm. 512, Boston, MA 02115. Phone: 617-732-6316; Fax: 617-732-5795; E-mail: damandelbr{at}bics.bwh.harvard.edu


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