Inhibition of phosphoantigen-mediated γδ T-cell proliferation by CD4+ CD25+ FoxP3+ regulatory T cells

Tumour growth promotes the expansion of CD4(+) CD25(+) FoxP3(+) regulatory T cells (Tregs) which suppress various arms of immune responses and might therefore contribute to tumour immunosurveillance. In this study, we found an inverse correlation between circulating Treg frequencies and phosphoantigen-induced gamma delta T-cell proliferation in cancer patients, which prompted us to address the role of Tregs in controlling the gamma delta T-cell arm of innate immune responses. In vitro, human Treg-peripheral blood mononuclear cell (PBMC) co-cultures strongly inhibited phosphoantigen-induced proliferation of gamma delta T cells and depletion of Tregs restored the impaired phosphoantigen-induced gamma delta T-cell proliferation of cancer patients. Tregs did not suppress other effector functions of gamma delta T cells such as cytokine production or cytotoxicity. Our experiments indicate that Tregs do not mediate their suppressive activity via a cell-cell contact-dependent mechanism, but rather secrete a soluble non-proteinaceous factor, which is independent of known soluble factors interacting with amino acid depletion (e.g. arginase-diminished arginine and indolamine 2,3-dioxygenase-diminished tryptophan) or nitric oxide (NO) production. However, the proliferative activity of alpha beta T cells was not affected by this cell-cell contact-independent suppressive activity induced by Tregs. In conclusion, these findings indicate a potential new mechanism by which Tregs can specifically suppress gamma delta T cells and highlight the strategy of combining Treg inhibition with subsequent gamma delta T-cell activation to enhance gamma delta T cell-mediated immunotherapy.