The cytokine receptor DR3 identifies and activates thymic NKT17 cells

Invariant natural killer T (iNKT) cells are thymus-generated T cells with innate-like characteristics and effector function. Several functionally distinct iNKT subsets have been identified, but NKT17 is the only iNKT subset that produces the proinflammatory cytokine IL-17. NKT17 cells are generated in the thymus and then exported into the periphery to populate lymphoid organs and barrier tissues, such as the lung, to provide critical support in host defense. However, the molecular mechanisms that drive the thymic development and subset-specific activation of NKT17 cells remain mostly unknown. Here, we identify the cytokine receptor DR3, a member of the TNF receptor superfamily, being selectively expressed on NKT17 cells but absent on all other thymic iNKT subsets. We further demonstrate that DR3 ligation leads to the in vivo activation of thymic NKT17 cells and provides in vitro costimulatory effects upon -GalCer-stimulation. Thus, our study reports the identification of a specific surface marker for thymic NKT17 cells that selectively triggers their activation both in vivo and in vitro. These findings provide new insights for deciphering the role and function of IL-17-producing NKT17 cells and for understanding the development and activation mechanisms of iNKT cells in general.