Inhibition of murine gamma delta lymphocyte expansion and effector function by regulatory alpha beta T cells is cell-contact-dependent and sensitive to GITR modulation

gamma delta T cells are highly cytolytic lymphocytes that produce large amounts of pro-inflammatory cytokines during immune responses to multiple pathogens. Furthermore, their ability to kill tumor cells has fueled the development of gamma delta-T-cell-based cancer therapies. Thus, the regulation of gamma delta-T-cell activity is of great biological and clinical relevance. Here, we show that murine CD4(+)CD25(+) alpha beta T cells, the vast majority of which express the Treg marker, Foxp3, abolish key effector functions of 78 T cells, namely the production of the pro-inflammatory cytokines, IFN-gamma and IL-17, cytotoxicity, and lymphocyte proliferation in vitro and in vivo. We further show that suppression is dependent on cellular contact between Treg and gamma delta T cells, results in the induction of an anergic state in gamma delta lymphocytes, and can be partially reversed by manipulating glucocorticoid-induced TNF receptor-related protein (GITR) signals. Our data collectively dissect a novel mechanism by which the expansion and pro-inflammatory functions of gamma delta T cells are regulated.