Human γδ Thymocytes Are Functionally Immature and Differentiate into Cytotoxic Type 1 Effector T Cells upon IL-2/IL-15 Signaling

Cytotoxicity and IFN-gamma production by human gamma delta T cells underlie their potent antitumor functions. However, it remains unclear where and how human gamma delta T cells acquire these key effector properties. Given the recent disclosure of a major contribution of the thymus to murine gamma delta T cell functional differentiation, in this study we have analyzed a series of human pediatric thymuses. We found that ex vivo-isolated gamma delta thymocytes produced negligible IFN-gamma 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 gamma delta T cells in cancer immunotherapy.