IFN-γ receptor and STAT1 signaling in B cells are central to spontaneous germinal center formation and autoimmunity.
IFN-γ receptor and STAT1 signaling in B cells are central to spontaneous germinal center formation and autoimmunity.
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DOI：
10.1084/jem.20151722
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发表时间：
2016-05-02
期刊：
影响因子：
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通讯作者：
Rahman ZS
中科院分区：
文献类型：
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作者：
Domeier PP;Chodisetti SB;Soni C;Schell SL;Elias MJ;Wong EB;Cooper TK;Kitamura D;Rahman ZS
通过STAT 1的B细胞固有IFN-γ受体信号传导是产生自发性生发中心所必需的，其可导致致病性自身抗体产生。自发开发的生发中心（GC [Spt-GC]）含有自身反应性B细胞，可产生体细胞突变和类别转换的致病性自身抗体（自身抗体），以促进自身免疫。然而，调节Spt-GC发展的机制尚不清楚。在这项研究中，我们报告，B细胞固有的IFN-γ受体（IFN-γR）和STAT 1信号是必需的Spt-GC和滤泡T辅助细胞（Tfh细胞）的发展。我们进一步证明IFN-γR和STAT 1信号通过驱动B细胞的T-bet表达和IFN-γ产生来控制Spt-GC和Tfh细胞的形成。与B6.Sle1B b小鼠相比，自身免疫性B6.Sle1B小鼠中的整体或B细胞特异性IFN-γR缺陷导致Spt-GC和Tfh细胞应答显著降低，导致抗核Ab反应性和IgG 2c和IgG 2 B自身Ab滴度降低。此外，我们观察到DNA反应性B细胞增殖和分化为GC B细胞表型需要B细胞固有的IFN-γR信号，这表明IFN-γR信号调节GC B细胞对核自身抗原的耐受性。然而，IFN-γR缺乏并不影响GC、Tfh细胞或针对T细胞依赖性外来抗原的Ab应答，表明IFN-γR信号传导调节自身免疫，但不调节外来抗原驱动的GC和Tfh细胞应答。总之，我们的数据定义了一个新的B细胞固有的IFN-γR信号通路特异性Spt-GC的发展和自身免疫。这种新的途径可以作为未来药物干预治疗系统性红斑狼疮的靶点。
B cell–intrinsic IFN-γ receptor signaling through STAT1 is required for the generation of spontaneous germinal centers, which can lead to pathogenic autoantibody production. Spontaneously developed germinal centers (GCs [Spt-GCs]) harbor autoreactive B cells that generate somatically mutated and class-switched pathogenic autoantibodies (auto-Abs) to promote autoimmunity. However, the mechanisms that regulate Spt-GC development are not clear. In this study, we report that B cell–intrinsic IFN-γ receptor (IFN-γR) and STAT1 signaling are required for Spt-GC and follicular T helper cell (Tfh cell) development. We further demonstrate that IFN-γR and STAT1 signaling control Spt-GC and Tfh cell formation by driving T-bet expression and IFN-γ production by B cells. Global or B cell–specific IFN-γR deficiency in autoimmune B6.Sle1b mice leads to significantly reduced Spt-GC and Tfh cell responses, resulting in diminished antinuclear Ab reactivity and IgG2c and IgG2b auto-Ab titers compared with B6.Sle1b mice. Additionally, we observed that the proliferation and differentiation of DNA-reactive B cells into a GC B cell phenotype require B cell–intrinsic IFN-γR signaling, suggesting that IFN-γR signaling regulates GC B cell tolerance to nuclear self-antigens. The IFN-γR deficiency, however, does not affect GC, Tfh cell, or Ab responses against T cell–dependent foreign antigens, indicating that IFN-γR signaling regulates autoimmune, but not the foreign antigen–driven, GC and Tfh cell responses. Together, our data define a novel B cell–intrinsic IFN-γR signaling pathway specific to Spt-GC development and autoimmunity. This novel pathway can be targeted for future pharmacological intervention to treat systemic lupus erythematosus.