TGF-β directly targets cytotoxic T cell functions during tumor evasion of immune surveillance

Summary escape from immune surveillance by producing the immunosuppressive cytokine TGF-β. However, the mechanism by which TGF-β inhibits T cell-mediated tumor clearance in vivo is unknown. We demonstrate that TGF-β acts on cytotoxic T lymphocytes (CTLs) to specifically inhibit the expression of five cytolytic gene products—namely, perforin, granzyme A, granzyme B, Fas ligand, and interferon γ—which are collectively responsible for CTL-mediated tumor cytotoxicity. Repression of granzyme B and interferon-γ involves binding of TGF-β-activated Smad and ATF1 transcription factors to their promoter regions, indicating direct and selective regulation by the TGF-β/Smad pathway. Neutralization of systemic TGF-β in mice enables tumor clearance with restoration of cytotoxic gene expression in antigen-specific CTLs in vivo. We suggest that TGF-β suppresses CTL function in vivo through an anticytotoxic program of transcriptional repression.