Harris Timothy J, Grosso Joseph F, Yen Hung-Rong, Xin Hong, Kortylewski Marcin, Albesiano Emilia, Hipkiss Edward L, Getnet Derese, Goldberg Monica V, Maris Charles H, Housseau Franck, Yu Hua, Pardoll Drew M, Drake Charles G
Department of Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21231, USA.
J Immunol. 2007 Oct 1;179(7):4313-7. doi: 10.4049/jimmunol.179.7.4313.
STAT3 activation has been observed in several autoimmune diseases, suggesting that STAT3-mediated pathways promote pathologic immune responses. We provide in vivo evidence that the fundamental role of STAT3 signaling in autoimmunity relates to its absolute requirement for generating T(H)17 T cell responses. We show that STAT3 is a master regulator of this pathogenic T cell subtype, acting at multiple levels in vivo, including T(H)17 T cell differentiation and cytokine production, as well as induction of RORgamma t and the IL-23R. Neither naturally occurring T(H)17 cells nor T(H)17-dependent autoimmunity occurs when STAT3 is ablated in CD4 cells. Furthermore, ablation of STAT3 signaling in CD4 cells results in increased T(H)1 responses, indicating that STAT3 signaling skews T(H) responses away from the T(H)1 pathway and toward the T(H)17 pathway. Thus, STAT3 is a candidate target for T(H)17-dependent autoimmune disease immunotherapy that could selectively inhibit pathogenic immune pathways.
在多种自身免疫性疾病中均观察到信号转导和转录激活因子3（STAT3）的激活，这表明STAT3介导的信号通路促进了病理性免疫反应。我们提供了体内证据，证明STAT3信号在自身免疫中的基本作用与其对产生辅助性T细胞17（T(H)17）应答的绝对需求有关。我们表明，STAT3是这种致病性T细胞亚群的主要调节因子，在体内多个水平发挥作用，包括T(H)17 T细胞分化和细胞因子产生，以及诱导维甲酸相关孤儿受体γt（RORγt）和白细胞介素23受体（IL-23R）。当CD4细胞中的STAT3被剔除时，既不会出现天然存在的T(H)17细胞，也不会发生T(H)17依赖的自身免疫。此外，CD4细胞中STAT3信号的剔除导致T(H)1应答增加，这表明STAT3信号使T(H)应答从T(H)1途径偏向T(H)17途径。因此，STAT3是T(H)17依赖的自身免疫性疾病免疫治疗的候选靶点，可选择性抑制致病性免疫途径。
