Type II but Not Type I IFN Signaling Is Indispensable for TLR7-Promoted Development of Autoreactive B Cells and Systemic Autoimmunity
Type II but Not Type I IFN Signaling Is Indispensable for TLR7-Promoted Development of Autoreactive B Cells and Systemic Autoimmunity
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DOI：
10.4049/jimmunol.1901175
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发表时间：
2020-02-15
影响因子：
4.4
通讯作者：
Rahman, Ziaur S. M.
中科院分区：
文献类型：
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作者：
Chodisetti, Sathi Babu;Fike, Adam J.;Rahman, Ziaur S. M.
TLR 7与系统性红斑狼疮（SLE）的发生有关，但其潜在机制尚不完全清楚。尽管已知TLR激活I型IFN（T1 IFN）信号传导，但T1 IFN和IFN-γ信号传导在TLR 7介导的Ab形成细胞（AFC）和生发中心（GC）应答的差异调节以及SLE发展中的作用从未被直接研究。使用TLR 7诱导和TLR 7过表达的SLE模型，我们在这项研究中报告了以前未被认识到的TLR 7诱导的IFN-γ信号在促进AFC和GC反应，导致自身反应性B细胞和SLE发展中不可或缺的作用。相比之下，T1 IFN信号传导仅适度地促进了这些小鼠中的自身免疫应答和疾病过程。TLR 7配体咪喹莫特处理的IFN-γ报告小鼠显示，包括滤泡辅助T（Tfh）细胞在内的CD 4（+）效应T细胞是TLR 7诱导的IFN-γ的主要生产者。来自咪喹莫特治疗的自身免疫易感B6.Sle1b小鼠的脾组织的转录组学分析表明，IFN-γ R充足和缺乏表明TLR 7诱导的IFN-γ激活多种信号通路来调节TLR 7促进的SLE。外周B细胞中Ifngr 1基因的条件性缺失进一步证明了TLR 7驱动的自身免疫AFC、GC和Tfh应答和SLE发展依赖于B细胞中的IFN-γ信号传导。最后，我们展示了STAT 1和T-bet在TLR 7驱动的GC、Tfh和浆细胞分化中至关重要的B细胞内在作用。总之，我们揭示了IFN-γ及其下游信号分子STAT 1和T-bet在B细胞中促进TLR 7驱动的AFC、GC和SLE发展中的非冗余作用，而T1 IFN信号对这些过程有一定的贡献。
TLR7 is associated with development of systemic lupus erythematosus (SLE), but the underlying mechanisms are incompletely understood. Although TLRs are known to activate type I IFN (T1IFN) signaling, the role of T1IFN and IFN-gamma signaling in differential regulation of TLR7-mediated Ab-forming cell (AFC) and germinal center (GC) responses, and SLE development has never been directly investigated. Using TLR7-induced and TLR7 overexpression models of SLE, we report in this study a previously unrecognized indispensable role of TLR7-induced IFN-gamma signaling in promoting AFC and GC responses, leading to autoreactive B cell and SLE development. T1IFN signaling in contrast, only modestly contributed to autoimmune responses and the disease process in these mice. TLR7 ligand imiquimod treated IFN-gamma reporter mice show that CD4(+) effector T cells including follicular helper T (Tfh) cells are the major producers of TLR7-induced IFN-gamma. Transcriptomic analysis of splenic tissues from imiquimod-treated autoimmune-prone B6.Sle1b mice sufficient and deficient for IFN-gamma R indicates that TLR7-induced IFN-gamma activates multiple signaling pathways to regulate TLR7-promoted SLE. Conditional deletion of Ifngr1 gene in peripheral B cells further demonstrates that TLR7-driven autoimmune AFC, GC and Tfh responses and SLE development are dependent on IFN-gamma signaling in B cells. Finally, we show crucial B cell-intrinsic roles of STAT1 and T-bet in TLR7-driven GC, Tfh and plasma cell differentiation. Altogether, we uncover a nonredundant role for IFN-gamma and its downstream signaling molecules STAT1 and T-bet in B cells in promoting TLR7-driven AFC, GC, and SLE development whereas T1IFN signaling moderately contributes to these processes.