Development and function of murine RORγt+ iNKT cells are under TGF-β signaling control

Invariant natural killer T (iNKT) cells have the ability to rapidly secret cytokines in response to diverse stimuli, and therefore influence numerous immune reactions. Although IFN-gamma and IL-4 are thought to dominate iNKT cytokine production, a distinct subset of iNKT cells, expressing ROR gamma t and producing IL-17, has now been identified in both mice and humans. Although a role in pathogen and allergic responses has been assigned to the ROR gamma t(+) iNKT subset, factors controlling their development and function remain illusive. Here, we demonstrate that ROR gamma t(+) iNKT-cell differentiation obeys transforming growth factor-beta (TGF-beta) signaling control, different from that described for conventional iNKT cells. We reveal that TGF-beta signaling, and particularly its SMAD4-dependent pathway, is required for both the survival of ROR gamma t(+) iNKT cells during their development and IL-17 production at the periphery. Moreover, constitutive TGF-beta signaling in ROR gamma t(+) iNKT cells drives higher peripheral numbers and increased tissue distribution. Finally, we found that SMAD4-dependent TGF-beta signaling is mandatory for the peripheral expansion of the ROR gamma t(+) iNKT cells responding to inflammatory signals. Thus, this work demonstrates that both the development and responsiveness of the newly described IL-17-producing iNKT cell subset is under the control of a dedicated TGF-beta signaling pathway. (Blood. 2012;119(15): 3486-3494)