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

Abstract

SummaryTumour 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 γδ T‐cell proliferation in cancer patients, which prompted us to address the role of Tregs in controlling the γδ T‐cell arm of innate immune responses. In vitro, human Treg–peripheral blood mononuclear cell (PBMC) co‐cultures strongly inhibited phosphoantigen‐induced proliferation of γδ T cells and depletion of Tregs restored the impaired phosphoantigen‐induced γδ T‐cell proliferation of cancer patients. Tregs did not suppress other effector functions of γδ 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 αβ 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 γδ T cells and highlight the strategy of combining Treg inhibition with subsequent γδ T‐cell activation to enhance γδ T cell‐mediated immunotherapy.

Part of CIRS Nexus · Curated by Lauren Lowenstein, The Biotoxin Lady

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