Lack of a role for transforming growth factor-[Beta] in cytotoxic T lymphocyte antigen-4-mediated inhibition of T cell activation

Similarities in the phenotypes of mice deficient for cytotoxic T lymphocyte antigen-4 (CTLA-4) or transforming growth factor-[Beta]1 (TGF-[Beta]1) and other observations have led to speculation that CTLA-4 mediates its inhibitory effect on T cell activation via costimulation of TGF-[Beta] production. Here, we examine the role of TGF-[Beta] in CTLA-4-mediated inhibition of T cell activation and of CTLA-4 in the regulation of TGF-[Beta] production. Activation of AND TCR transgenic mouse T cells with costimulatory receptor-specific antigen presenting cells results in efficient costimulation of proliferation by CD28 ligation and inhibition by CTLA-4 ligation. Neutralizing antibody to TGF-[Beta] does not reverse CTLA-4-mediated inhibition. Also, CTLA-4 ligation equally inhibits proliferation of wild-type, TGF-[Beta][1.sup.-/-], and [Smad3.sup.-/-] T cells. Further, CTLA-4 engagement does not result in the increased production of either latent or active TGF-[Beta] by [CD4.sup.+] T cells. These results indicate that CTLA-4 ligation does not regulate TGF-[Beta] production and that CTLA-4-mediated inhibition can occur independently of TGF-[Beta]. Collectively, these data demonstrate that CTLA-4 and TGF-[Beta] represent distinct mechanisms for regulation of T cell responses.