T cell-derived inducible nitric oxide synthase switches offth17 cell differentiation

RORγt is necessary for the generation of T_H17 cells but the molecular mechanisms for the regulation of T_H17 cells are still not fully understood. We show that activation of CD4+ T cells results in the expression of inducible nitric oxide synthase (iNOS). iNOS-deficient mice displayed enhanced T_H17 cell differentiation but without major effects on either T_H1 or T_H2 cell lineages, whereas endothelial NOS (eNOS) or neuronal NOS (nNOS) mutant mice showed comparable T_H17 cell differentiation compared with wild-type control mice. The addition of N6-(1-iminoethyl)-l-lysine dihydrochloride (L-NIL), the iNOS inhibitor, significantly enhanced T_H17 cell differentiation, and S-nitroso-N-acetylpenicillamine (SNAP), the NO donor, dosedependently reduced the percentage of IL-17-producing CD4⁺ T cells. NO mediates nitration of tyrosine residues in RORγt, leading to the suppression of RORγt-induced IL-17 promoter activation, indicating that NO regulates IL-17 expression at the transcriptional level. Finally, studies of an experimental model of colitis showed that iNOS deficiency results in more severe inflammation with an enhanced T_H17 phenotype. These results suggest that NO derived from iNOS in activated T cells plays a negative role in the regulation of T_H17 cell differentiation and highlight the importance of intrinsic programs for the control of T_H17 immune responses.