B cell IFN-γ receptor signaling promotes autoimmune germinal centers via cell-intrinsic induction of BCL-6.
B cell IFN-γ receptor signaling promotes autoimmune germinal centers via cell-intrinsic induction of BCL-6.
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DOI：
10.1084/jem.20151724
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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：
Rawlings DJ
中科院分区：
文献类型：
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作者：
Jackson SW;Jacobs HM;Arkatkar T;Dam EM;Scharping NE;Kolhatkar NS;Hou B;Buckner JH;Rawlings DJ
Jackson等人提出B细胞内禀IFN-γ受体信号在自发生发中心激活和自身抗体产生中的作用。生发中心（GC）反应失调与人类自身免疫性疾病的发病机制有关，包括系统性红斑狼疮（SLE）。虽然1型和2型干扰素（ifn）都参与狼疮的发病机制，但它们各自对自身免疫性GCs建立的影响尚未得到解决。在这项研究中，使用B细胞驱动的自身免疫嵌合模型，我们证明了B细胞1型IFN受体信号加速狼疮的发展，但不是必需的。相反，作为抗原呈递细胞的B细胞启动CD4+ T细胞激活和IFN-γ产生，并且引人注目的是，B细胞内在的IFN-γ受体（IFN-γ r）缺失会消除自身免疫GCs、类转换自身抗体（auto-Abs）和全身自身免疫。从机制上讲，虽然IFN-γR信号增加了B细胞T-bet的表达，但B细胞固有的T-bet缺失对致病性自身ab亚类的类转换重组产生孤立的影响，而不影响GC的发展。相反，在小鼠和人B细胞中，IFN-γ与B细胞受体、toll样受体和/或CD40激活信号协同作用，促进细胞内GC主转录因子、B细胞淋巴瘤6蛋白的表达。我们的综合研究结果确定了一种新的B细胞内在机制，IFN信号促进狼疮发病，暗示该途径是SLE的潜在治疗靶点。
Jackson et al. propose a role for B cell–intrinsic IFN-γ receptor signaling in spontaneous germinal center activation and autoantibody production. Dysregulated germinal center (GC) responses are implicated in the pathogenesis of human autoimmune diseases, including systemic lupus erythematosus (SLE). Although both type 1 and type 2 interferons (IFNs) are involved in lupus pathogenesis, their respective impacts on the establishment of autoimmune GCs has not been addressed. In this study, using a chimeric model of B cell-driven autoimmunity, we demonstrate that B cell type 1 IFN receptor signals accelerate, but are not required for, lupus development. In contrast, B cells functioning as antigen-presenting cells initiate CD4+ T cell activation and IFN-γ production, and strikingly, B cell–intrinsic deletion of the IFN-γ receptor (IFN-γR) abrogates autoimmune GCs, class-switched autoantibodies (auto-Abs), and systemic autoimmunity. Mechanistically, although IFN-γR signals increase B cell T-bet expression, B cell–intrinsic deletion of T-bet exerts an isolated impact on class-switch recombination to pathogenic auto-Ab subclasses without impacting GC development. Rather, in both mouse and human B cells, IFN-γ synergized with B cell receptor, toll-like receptor, and/or CD40 activation signals to promote cell-intrinsic expression of the GC master transcription factor, B cell lymphoma 6 protein. Our combined findings identify a novel B cell–intrinsic mechanism whereby IFN signals promote lupus pathogenesis, implicating this pathway as a potential therapeutic target in SLE.