Engagement of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) induces transforming growth factor beta (TGF-beta) production by murine CD4(+) T cells

Evidence indicates that cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) may negatively regulate T cell activation, but the basis for the inhibitory effect remains unknown. We report here that cross-linking of CTLA-4 induces transforming growth factor beta (TGF-beta) production by murine CD4(+) T cells. CD4(+) T helper type 1 (Th1), Th2, and Th0 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, include inhibition of T cell proliferation and interleukin (IL)-2 secretion, as well as suppression of both interferon gamma (Th1) and IL-4 (Th2). Moreover, addition of anti-TGF-beta partially reverses this T cell suppression. When CTLA-4 was cross-linked in T cell populations from TGF-beta1 gene-deleted (TGF-beta1(-/-)) mice, the T cell responses were only suppressed 38% compared with 95% in wild-type mice. Our data demonstrate that engagement of CTLA-4 leads to CD4(+) T cell production of TGF-beta, which, in part, contributes to the downregulation of T cell activation. CTLA-4, through TGF-beta, may serve as a counterbalance for CD28 costimulation of IL-2 and CD4(+) T cell activation.