T cell-derived inducible nitric oxide synthase switches off TH17 cell differentiation

被引：99

作者：

Yang, Jianjun ^{[1
]}

Zhang, Ruihua ^{[1
]}

Lu, Geming ^{[1
]}

Shen, Yu ^{[1
]}

Peng, Liang ^{[1
]}

Zhu, Chen ^{[5
]}

Cui, Miao ^{[1
]}

Wang, Weidong ^{[6
]}

Arnaboldi, Paul ^{[1
]}

Tang, Meng ^{[7
]}

Gupta, Monica ^{[8
]}

Qi, Chen-Feng

Jayaraman, Padmini ^{[1
,2
]}

Zhu, Hongfa ^{[3
]}

Jiang, Bo ^{[1
]}

Chen, Shu-hsia ^{[1
]}

He, John Cijiang ^{[1
]}

Ting, Adrian T. ^{[1
]}

Zhou, Ming-Ming ^{[4
]}

Kuchroo, Vijay K. ^{[5
]}

Morse, Herbert C., III ^{[9
]}

Ozato, Keiko ^{[8
]}

Sikora, Andrew G. ^{[1
,2
]}

Xiong, Huabao ^{[1
]}

机构：

[1] Mt Sinai Sch Med, Dept Med, Inst Immunol, New York, NY 10029 USA

[2] Mt Sinai Sch Med, Dept Otolaryngol Head & Neck Surg, New York, NY 10029 USA

[3] Mt Sinai Sch Med, Dept Pathol, New York, NY 10029 USA

[4] Mt Sinai Sch Med, Dept Struct & Chem Biol, New York, NY 10029 USA

[5] Harvard Univ, Sch Med, Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA

[6] Cornell Univ, Weill Med Coll, Ronald O Perelman & Claudia Cohen Ctr Reprod Med, New York, NY 10021 USA

[7] Southeast Univ, Sch Publ Hlth, Minist Educ, Key Lab Environm Med & Engn, Nanjing 210009, Jiangsu, Peoples R China

[8] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Programs Genom Differentiat, Bethesda, MD 20892 USA

[9] NIAID, Immunogenet Lab, NIH, Bethesda, MD 20892 USA

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2013年 / 210卷 / 07期

基金：

中国国家自然科学基金; 美国国家卫生研究院;

关键词：

CENTRAL-NERVOUS-SYSTEM; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; KAPPA-B ACTIVATION; HELPER-CELLS; TH17; CELLS; TGF-BETA; EXPERIMENTAL STROKE; TYROSINE NITRATION; INFLAMMATION; RECEPTOR;

D O I：

10.1084/jem.20122494

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

ROR gamma t is necessary for the generation of T(H)17 cells but the molecular mechanisms for the regulation of T(H)17 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(H)17 cell differentiation but without major effects on either T(H)1 or T(H)2 cell lineages, whereas endothelial NOS (eNOS) or neuronal NOS (nNOS) mutant mice showed comparable T(H)17 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(H)17 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 ROR gamma t, leading to the suppression of ROR gamma t-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(H)17 phenotype. These results suggest that NO derived from iNOS in activated T cells plays a negative role in the regulation of T(H)17 cell differentiation and highlight the importance of intrinsic programs for the control of T(H)17 immune responses.

引用

页码：1447 / 1462

页数：16

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