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

Jianjun Yang, Ruihua Zhang, Geming Lu, Yu Shen, Liang Peng, Chen Zhu, Miao Cui, Weidong Wang, Paul Arnaboldi, Meng Tang, Monica Gupta, Chen Feng Qi, Padmini Jayaraman, Hongfa Zhu, Bo Jiang, Shu hsia Chen, John Cijiang He, Adrian T. Ting, Ming Ming Zhou, Vijay K. KuchrooHerbert C. Morse, Keiko Ozato, Andrew G. Sikora, Huabao Xiong

Research output: Contribution to journalArticle

71 Scopus citations

Abstract

RORγt is necessary for the generation of TH17 cells but the molecular mechanisms for the regulation of TH17 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 TH17 cell differentiation but without major effects on either TH1 or TH2 cell lineages, whereas endothelial NOS (eNOS) or neuronal NOS (nNOS) mutant mice showed comparable TH17 cell differentiation compared with wild-type control mice. The addition of N6-(1-iminoethyl)-l-lysine dihydrochloride (L-NIL), the iNOS inhibitor, significantly enhanced TH17 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 TH17 phenotype. These results suggest that NO derived from iNOS in activated T cells plays a negative role in the regulation of TH17 cell differentiation and highlight the importance of intrinsic programs for the control of TH17 immune responses.

Original languageEnglish (US)
Pages (from-to)1447-1462
Number of pages16
JournalJournal of Experimental Medicine
Volume210
Issue number7
DOIs
StatePublished - Jul 2013

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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