T细胞中的白细胞介素-6-糖蛋白130-信号转导子和转录激活子3在稳态下指导白细胞介素-17⁺辅助性T细胞的发育,对调节性T细胞的发育影响最小。
IL-6-gp130-STAT3 in T cells directs the development of IL-17+ Th with a minimum effect on that of Treg in the steady state.
作者信息
Nishihara Mika, Ogura Hideki, Ueda Naoko, Tsuruoka Mineko, Kitabayashi Chika, Tsuji Fumio, Aono Hiroyuki, Ishihara Katsuhiko, Huseby Eric, Betz Ulrich A K, Murakami Masaaki, Hirano Toshio
机构信息
Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, Osaka, Japan.
出版信息
Int Immunol. 2007 Jun;19(6):695-702. doi: 10.1093/intimm/dxm045. Epub 2007 May 9.
IL-17-producing Th (Th17) comprise a distinct lineage of pro-inflammatory Th that are major contributors to autoimmune diseases. Treatment with IL-6 and transforming growth factor beta (TGFbeta) induces naive CD4+ T cells to generate Th17, which also requires expression of the IL-6/TGFbeta target RORgammat. We reported that IL-6 transduces two signaling pathways via tyrosine redidues of the signal transducer gp130: one depends on signal transducers and activators of transcription (STAT)-3 activation and the other on Src homology region 2 domain-containing phosphatase 2 (SHP2)/Grb2 associated binder (Gab)/mitogen-activated protein kinase (MAPK) activation. Here, we showed that CD4+ T cells carrying a mutant gp130 that transduces the SHP2/Gab/MAPK pathway but not the STAT3-mediated one failed to develop into Th17, while CD4+ T cells whose mutant gp130 transduces the STAT3 signal only generated Th17, indicating that IL-6 acts directly on T cells through the tyrosine residues of gp130 required for STAT3 activation to promote the development of Th17. Moreover, we found that gp130-STAT3 pathway is essential for Th17 development and for the expression of RORgammat by using T cells specifically lacking gp130 and STAT3. Noteworthy is that the regulatory T cell (Treg) percentages and numbers were comparable between all mutant mice we tested in vivo, although we showed that IL-6-gp130-STAT3 pathway suppressed Treg development in vitro. Thus, we conclude that IL-6 acts directly to promote the development of Th17 by activating the T cell gp130-STAT3 pathway but has a minimum effect on Treg development at least in the steady state in vivo. Therefore, blockade of IL-6-gp130-STAT3 pathway in CD4+ T cells could be a good target for controlling unwanted Th17-mediated immune responses including autoimmune diseases.
产生白细胞介素17的辅助性T细胞(Th17)构成了促炎性辅助性T细胞的一个独特谱系,是自身免疫性疾病的主要促成因素。用白细胞介素6和转化生长因子β(TGFβ)进行处理可诱导初始CD4+ T细胞生成Th17,这还需要白细胞介素6/TGFβ靶标维甲酸相关孤核受体γt(RORγt)的表达。我们报道过,白细胞介素6通过信号转导子gp130的酪氨酸残基转导两条信号通路:一条依赖于信号转导及转录激活因子(STAT)-3的激活,另一条依赖于含Src同源区2结构域的磷酸酶2(SHP2)/Grb2相关结合蛋白(Gab)/丝裂原活化蛋白激酶(MAPK)的激活。在此,我们表明,携带一种突变型gp130的CD4+ T细胞转导SHP2/Gab/MAPK通路但不转导STAT3介导的通路,无法发育为Th17,而其突变型gp130仅转导STAT3信号的CD4+ T细胞则只生成Th17,这表明白细胞介素6通过STAT3激活所需的gp130酪氨酸残基直接作用于T细胞,以促进Th17的发育。此外,我们发现,通过使用特异性缺乏gp130和STAT3的T细胞,gp130-STAT3通路对Th17的发育以及RORγt的表达至关重要。值得注意的是,尽管我们表明白细胞介素6-gp130-STAT3通路在体外会抑制调节性T细胞(Treg)的发育,但在体内我们测试的所有突变小鼠中,Treg的百分比和数量相当。因此,我们得出结论,白细胞介素6通过激活T细胞gp130-STAT3通路直接促进Th17的发育,但至少在体内稳态时对Treg的发育影响最小。因此,阻断CD4+ T细胞中的白细胞介素6-gp130-STAT3通路可能是控制包括自身免疫性疾病在内的不必要的Th17介导的免疫反应的一个良好靶点。