ENGAGEMENT OF CYTOTOXIC T LYMPHOCYTE-ASSOCIATED ANTIGEN 4 (CTLA-4) INDUCES TRANSFORMING-GROWTH-FACTOR-BETA (TGF-BETA) PRODUCTION BY MURINE CD4(-CELLS() T)

Evidence indicates that cytotoxic T lymphocyte-associated antigen 4 (C TLA-4) may negatively regulate T cell activation, bur the basis for th e inhibitory effect remains unknown. We report here that cross-linking of CTLA-4 induces transforming growth factor beta (TGF-beta) producti on by murine CD4(+) T cells. CD4(+) T helper type 1 (Th1), Th2, and Th 0 clones all secrete TGF-beta after antibody cross-linking of CTLA-4, indicating that induction of TGF-beta by CTLA-4 signaling represents a ubiquitous feature of murine CD4(+) T cells. Stimulation of the CD3-T cell antigen receptor complex does not independently induce TGF-beta, but is required for optimal CTLA-4-mediated TGF-beta production. The consequences of cross-linking of CTLA-4, together with CD3 and CD28, i nclude inhibition of T cell proliferation and interleukin (IL)-2 secre tion, as well as suppression of both interferon gamma (Th1) and IL-4 ( Th2). Moreover, addition of anti-TGF-beta partially reverses this T ce ll suppression. When CTLA-4 was cross-linked in T cell populations fro m TGF-beta 1 gene-deleted (TGF-beta 1(-/-)) mice, the T cell responses were only suppressed 38% compared with 95% in wild-type mice. Our dat a demonstrate that engagement of CTLA-4 leads to CD4(+) T cell product ion of TGF-beta, which, in part, contributes to the downregulation of T cell activation. CTLA-4, through TGF-beta, may serve as a counterbal ance for CD28 costimulation of IL-2 and CD4(+) T cell activation.