Notch-Hes1 pathway is required for the development of IL-17-producing γδ T cells

Unlike conventional T cells, which are exported from the thymus as naive cells and acquire effector functions upon antigen encounter in the periphery, a subset of gamma delta T cells differentiates into effectors that produce IL-17 within the fetal thymus. We demonstrate here that intrathymic development of the naturally occurring IL-17-producing gamma delta T cells is independent of STAT3 and partly dependent on ROR gamma t. Comparative gene-expression analysis identified Hes1, one of the basic helix-loop-helix proteins involved in Notch signaling, as a factor specifically expressed in IL-17-producing gamma delta T cells. Hes1 is critically involved in the development of IL-17-producing gamma delta T cells, as evidenced by their severe decrease in the thymi of Hes1-deficient fetal mice. Delta-like 4 (Dll4)-expressing stromal cells support the development of IL-17-producing gamma delta T cells in vitro. In addition, conditional Hes1 ablation in peripheral gamma delta T cells decreases their IL-17 production but not their IFN-gamma production. These results reveal a unique differentiation pathway of IL-17-producing gamma delta T cells. (Blood. 2011;118(3):586-593)