Ribot, Julie C.Ribeiro, Sérgio T.Correia, Daniel V.Sousa, Ana E.Silva-Santos, Bruno2015-09-222015-09-222014The Journal of Immunology, March 1, 2014, vol. 192 no. 5 2237-22430022-1767http://dx.doi.org/10.4049/jimmunol.1303119http://hdl.handle.net/10451/20121© 2014 by The American Association of Immunologists, Inc.Cytotoxicity and IFN-γ production by human γδ T cells underlie their potent antitumor functions. However, it remains unclear where and how human γδ T cells acquire these key effector properties. Given the recent disclosure of a major contribution of the thymus to murine γδ T cell functional differentiation, in this study we have analyzed a series of human pediatric thymuses. We found that ex vivo-isolated γδ thymocytes produced negligible IFN-γ and lacked cytolytic activity against leukemia cells. However, these properties were selectively acquired upon stimulation with IL-2 or IL-15, but not IL-4 or IL-7. Unexpectedly, TCR activation was dispensable for these stages of functional differentiation. The effects of IL-2/IL-15 depended on MAPK/ERK signaling and induced de novo expression of the transcription factors T-bet and eomesodermin, as well as the cytolytic enzyme perforin, required for the cytotoxic type 1 program. These findings have implications for the manipulation of γδ T cells in cancer immunotherapy.engjournal article