RORγt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation

被引:937
作者
Codarri, Laura [1 ]
Gyuelveszi, Gabor [1 ]
Tosevski, Vinko [1 ]
Hesske, Lysann [2 ]
Fontana, Adriano [1 ]
Magnenat, Laurent [3 ]
Suter, Tobias [2 ]
Becher, Burkhard [1 ]
机构
[1] Univ Zurich, Inst Expt Immunol, CH-8091 Zurich, Switzerland
[2] Univ Zurich Hosp, CH-8091 Zurich, Switzerland
[3] Merck Serono Res, Prot Engn & Antibody Technol, Geneva, Switzerland
基金
瑞士国家科学基金会;
关键词
COLONY-STIMULATING FACTOR; TH17; CELLS; TGF-BETA; IFN-GAMMA; DISTINCT; INFLAMMATION; CNS; IL-23; DIFFERENTIATION; ACTIVATION;
D O I
10.1038/ni.2027
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Although the role of the T(H)1 and T(H)17 subsets of helper T cells as disease mediators in autoimmune neuroinflammation remains a subject of some debate, none of their signature cytokines are essential for disease development. Here we report that interleukin 23 (IL-23) and the transcription factor ROR gamma t drove expression of the cytokine GM-CSF in helper T cells, whereas IL-12, interferon-gamma (IFN-gamma) and IL-27 acted as negative regulators. Autoreactive helper T cells specifically lacking GM-CSF failed to initiate neuroinflammation despite expression of IL-17A or IFN-gamma, whereas GM-CSF secretion by Ifng(-/-)Il17a(-/-)helper T cells was sufficient to induce experimental autoimmune encephalomyelitis (EAE). During the disease effector phase, GM-CSF sustained neuroinflammation via myeloid cells that infiltrated the central nervous system. Thus, in contrast to all other known helper T cell-derived cytokines, GM-CSF serves a nonredundant function in the initiation of autoimmune inflammation regardless of helper T cell polarization.
引用
收藏
页码:560 / U248
页数:9
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