Inhibition of murine γδ lymphocyte expansion and effector function by regulatory αβ T cells is cell-contact-dependent and sensitive to GITR modulation

© 2010 WILEYγδ 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 γδ-T-cell-based cancer therapies. Thus, the regulation of γδ-T-cell activity is of great biological and clinical relevance. Here, we show that murine CD4+CD25+ αβ T cells, the vast majority of which express the Treg marker, Foxp3, abolish key effector functions of γδ T cells, namely the production of the pro-inflammatory cytokines, IFN-γ 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 γδ T cells, results in the induction of an anergic state in γδ 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 γδ T cells are regulated.This work was supported by grant PTDC/SAU-MII/71662/2006 from Fundação para a Ciência e a Tecnologia (FCT), who also provided individual fellowships to J.C.R., A.dB., D.V.C. and I.C., and by an Installation Grant from the European Molecular Biology Organization (YIP Project 1440)