T cell-derived inducible nitric oxide synthase switches off Th17 cell differentiation (P1225)

Abstract

Abstract Although it is clear that RORgt is necessary for the generation of Th17 cells, the molecular mechanisms for the regulation of Th17 cell. here, we show that activation of CD4+ T cells results in the expression of inducible nitric oxide synthase (iNOS), but not endothelial NOS (eNOS) or neuronal NOS (nNOS). iNOS deficient mice displayed enhanced Th17 cell differentiation but without major effects on either Th1 or Th2 cell lineages, while eNOS or nNOS mutant mice showed comparable Th17 cell differentiation compared to wild type control mice. Addition of dihydrochloride (L-NIL), the iNOS inhibitor, significantly enhanced Th17 cell differentiation and S-nitroso-N-acetylpenicillamine (SNAP), the NO donor, dose-dependently reduced the percentage of IL-17-producing CD4+ T cells. NO mediates nitration of tyrosine residues in RORgt leading to the suppression of RORgt-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 Th17 phenotype. These results suggest that NO derived from iNOS by activated T cells plays a negative role in the regulation of Th17 cell differentiation and highlight the important of intrinsic programs for the control of Th17 immune responses.