Phosphoantigen-Stimulated gamma delta T Cells Suppress Natural Killer-Cell Responses to Missing-Self

gamma delta T cells stimulated by phosphoantigens (pAg) are potent effectors that secrete Th1 cytokines and kill tumor cells. Consequently, they are considered candidates for use in cancer immunotherapy. However, they have proven only moderately effective in several clinical trials. We studied the consequences of pAg-stimulated gamma delta T-cell interactions with natural killer (NK) cells and CD8(+) T cells, major innate and adaptive effectors, respectively. We found that pAg-stimulated gamma delta T cells suppressed NK-cell responses to "missing-self" but had no effect on antigen-specific CD8(+) T-cell responses. Extensive analysis of the secreted cytokines showed that pAg-stimulated gamma delta T cells had a proinflammatory profile. CMV-pp65-specific CD8(+) T cells primed with pAg-stimulated gamma delta T cells showed little effect on responses to pp65-loaded target cells. By contrast, NK cells primed similarly with gamma delta T cells had impaired capacity to degranulate and produce IFN gamma in response to HLA class I-deficient targets. This effect depended on BTN3A1 and required direct contact between NK cells and gamma delta T cells. gamma delta T-cell priming of NK cells also led to a downregulation of NKG2D and NKp44 on NK cells. Every NK-cell subset was affected by gamma delta T cell-mediated immunosuppression, but the strongest effect was on KIR(+)NKG2A(-) NK cells. We therefore report a previously unknown function for gamma delta T cells, as brakes of NK-cell responses to "missing-self." This provides a new perspective for optimizing the use of gamma delta T cells in cancer immunotherapy and for assessing their role in immune responses to pAg-producing pathogens.