B7-1 or B7-2 is required to produce the lymphoproliferative phenotype in mice lacking cytotoxic T lymphocyte-associated antigen 4 (CTLA-4)

The costimulatory molecules B7-1 and B7-2 regulate T lymphocyte activation by delivering activating signals through CD28 and inhibitory signals throug h cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). The importance of C TLA-4-mediated inhibition was demonstrated by the uncontrolled T cell activ ation and lymphoproliferative disease that develops in CTLA-4-deficient (-/ -) mice. To examine the role of B7 signaling in the activation of CTLA-4-de fcient T cells, we bred CTLA-4(-/-) mice with mice lacking B7-1, B7-2, or b oth B7 molecules. The CTLA-4/B7-1(-/-) and the CTLA-4/B7-2(-/-) mice develo p 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 infiltr ates in any organs, or increased T cell activation. Therefore, the two B7 m olecules have overlapping functions, since either B7-1 or B7-2 alone can ca use the CTLA-4(-/-) phenotype. Elimination of both B7-1 and B7-2 from the C TLA-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 treat ment. This suggests that the inhibitory function of CTLA-4 can overcome str ong CD28-mediated signaling in vivo.