Expansion of T follicular helper-T helper 1 like cells through epigenetic regulation by signal transducer and activator of transcription factors
Expansion of T follicular helper-T helper 1 like cells through epigenetic regulation by signal transducer and activator of transcription factors
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DOI：
10.1136/annrheumdis-2017-212652
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发表时间：
2018-09-01
影响因子：
27.4
通讯作者：
Tanaka, Yoshiya
中科院分区：
文献类型：
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作者：
Ma, Xiaoxue;Nakayamada, Shingo;Tanaka, Yoshiya
目的滤泡辅助性T细胞（Tfh）在系统性红斑狼疮（SLE）的发生、发展中起重要作用。为了评估Tfh细胞分化的特点和机制，我们研究了SLE患者T辅助细胞的表型和潜在的表观遗传修饰，由精氨酸诱导的信号转导和转录激活因子（STAT）familyfactors.Methods外周血单个核细胞从患者和健康供体进行了流式细胞仪分析。分离CD 4（+）T细胞并在各种刺激下培养。流式细胞术和定量PCR分析特征性标志物的表达和STATs的磷酸化。结果IL-12诱导的STAT 1和STAT 4同时激活可诱导CD 4（+）CXCR 5（+）CXCR 3（+）Bcl-6（+）T-bet（+）IL-21（+）IFN-γ（+）Tfh-Th 1样细胞分化。STAT结合位点的Bcl-6和T-bet位点通过二价组蛋白修饰来标记。在IL-12刺激后，STAT 1和STAT 4都直接结合在BCL 6和TBX 21基因位点上，伴随着抑制性组蛋白标记三甲基化组蛋白3赖氨酸27的抑制。SLE患者血清IL-12、IFN-γ水平、IL-12受体表达及CXCR 5（+）、CXCR 3（+）激活的Tfh-Th 1样细胞比例均升高。结论IL-12介导的STAT 1和STAT 4共激活改变了SLE患者组蛋白的修饰，导致SLE患者Tfh-Th 1样细胞的分化。这可能是Tfh-Th 1样细胞扩增的潜在机制之一，并可能有助于开发SLE的细胞特异性治疗。
Objectives T follicular helper (Tfh) cells are critical in the development and progression of systemic lupus erythematosus (SLE). To assess the characteristics and mechanisms of differentiation of Tfh cells, we investigated the phenotype of T helper cells in patients with SLE and underlying epigenetic modifications by cytokine-induced signal transducer and activators of transcription (STAT) family factors.Methods Peripheral blood mononuclear cells from patients and healthy donors were analysed by flow cytometry. CD4(+) T cells were isolated and cultured under various stimulations. Expression of characteristic markers and phosphorylation of STATs were analysed by flow cytometry and quantitative PCR. Histone modifications were analysed by chromatin immunoprecipitation (ChIP)-PCR.Results Differentiation of CD4(+)CXCR5(+ )CXCR3(+)Bcl-6(+)T-bet(+) IL-21(+)IFN-gamma(+)Tfh-Th1-like cells was induced by interleukin (IL)-12-induced activation of STAT1 and STAT4 simultaneously. The loci of Bcl-6 and T-bet at STAT binding sites were marked by bivalent histone modifications. After IL-12 stimulation, both STAT1 and STAT4 directly bound on BCL6 and TBX21 gene loci accompanied by suppression of repressive histone mark trimethylated histone 3 lysine 27. Levels of serum IL-12 and interferon (IFN)-gamma, expression of IL-12 receptors and proportion of CXCR5(+)CXCR3(+) activated Tfh-Th1-like cells were increased in patients with SLE. Furthermore, the level of pSTAT1, pSTAT4 and T-bet were higher in activated Tfh-Th1-like cells than non-Tfh-Th1 cells.Conclusion Our findings suggest that IL-12-mediated co-activation of STAT1 and STAT4 alters histone modification, resulting in differentiation of Tfh-Th1-like cells that are characteristically expanded in patients with SLE. This could be one of the underlying mechanisms responsible for expansion of Tfh-Th1-like cells and potentially helpful towards development of cell-specific treatment for SLE.