J. Exp. Med., Volume 188, Number 10, November 16, 1998 1849-1857

Engagement of Cytotoxic T Lymphocyte-associated Antigen 4 (CTLA-4) Induces Transforming Growth Factor  (TGF-) Production by Murine CD4⁺ T Cells

By Wanjun Chen, Wenwen Jin, and Sharon M. Wahl

From the Oral Infection and Immunity Branch, National Institute of Dental Research, National Institutes of Health, Bethesda, Maryland 20892

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  (TGF-) production by murine CD4⁺ T cells. CD4⁺ T helper type 1 (Th1), Th2, and Th0 clones all secrete TGF- after antibody cross-linking of CTLA-4, indicating that induction of TGF- 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-, but is required for optimal CTLA-4-mediated TGF- 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  (Th1) and IL-4 (Th2). Moreover, addition of anti-TGF- partially reverses this T cell suppression. When CTLA-4 was cross-linked in T cell populations from TGF-1 gene-deleted (TGF-1^/) 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-, which, in part, contributes to the downregulation of T cell activation. CTLA-4, through TGF-, may serve as a counterbalance for CD28 costimulation of IL-2 and CD4⁺ T cell activation.

CD4⁺  T cells;  cytotoxic T lymphocyte-associated antigen 4;  transforming growth factor

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