Abstract
The differentiation and maintenance of Th17 cells require a unique cytokine milieu and activation of lineage-specific transcription factors. This process appears to be antagonized by the transcription factor T-bet, which controls the differentiation of Th1 cells. Considering that T-bet-deficient (T-bet(-/-) ) mice are largely devoid of natural killer (NK) cells due to a defect in the terminal maturation of these cells, and because NK cells can influence the differentiation of T helper cells, we investigated whether the absence of NK cells in T-bet-deficient mice contributes to the augmentation of autoreactive Th17 cell responses. We show that the loss of T-bet renders the transcription factors Rorc and STAT3 highly responsive to activation by stimuli provided by NK cells. Furthermore, reconstitution of T-bet(-/-) mice with wild-type NK cells inhibited the development of autoreactive Th17 cells through NK cell-derived production of IFN-γ. These results identify NK cells as critical regulators in the development of autoreactive Th17 cells and Th17-mediated pathology.