Phosphoantigens Overcome Human TCRVγ9+ γδ Cell Immunosuppression by TGF-β: Relevance for Cancer Immunotherapy

Human gamma delta cells expressing TCRV gamma 9 are HLA-unrestricted CTLs with high relevance for cancer immunotherapy. Many tumor cell types produce TGF-beta, however, a cytokine strongly immunosuppressive for conventional T CD4, CD8, and NK cells. Whether TGF-beta also inhibits TCRV gamma 9(+) lymphocytes was unknown. Because phosphoantigens (PAgs), such as bromohydrin pyrophosphate, selectively activate the antitumor functions of TCRV gamma 9(+) T cells, in this study, we investigated whether TGF-beta modulates these functions. We report that TGF-beta does not block activation of TCRV gamma 9(+) T cells but inhibits their PAg/IL-2-induced proliferation and maturation into effector cells and finally reduces the cytotoxic activity of these gamma delta T cells when exposed to lymphoma target cells. TGF-beta did not bias their differentiation pattern toward gamma delta Th17 or gamma delta regulatory T cells. Nevertheless, increasing doses of PAg stimulus countered TGF-beta inhibition. So, although TGF-beta impairs TCRV gamma 9(+) gamma delta cells like other cytolytic lymphocytes, PAg alone or combined to therapeutic mAb has the ability to bypass its immunosuppressive activity. The Journal of Immunology, 2010, 184: 6680-6687.