Chodisetti Sathi Babu, Fike Adam J, Domeier Phillip P, Singh Harinder, Choi Nicholas M, Corradetti Chelsea, Kawasawa Yuka Imamura, Cooper Timothy K, Caricchio Roberto, Rahman Ziaur S M
Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033.
J. Craig Venter Institute, Rockville, MD 20850.
J Immunol. 2020 Feb 15;204(4):796-809. doi: 10.4049/jimmunol.1901175. Epub 2020 Jan 3.
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-γ 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-γ 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-γ reporter mice show that CD4 effector T cells including follicular helper T (Tfh) cells are the major producers of TLR7-induced IFN-γ. Transcriptomic analysis of splenic tissues from imiquimod-treated autoimmune-prone B6.Sle1b mice sufficient and deficient for IFN-γR indicates that TLR7-induced IFN-γ activates multiple signaling pathways to regulate TLR7-promoted SLE. Conditional deletion of gene in peripheral B cells further demonstrates that TLR7-driven autoimmune AFC, GC and Tfh responses and SLE development are dependent on IFN-γ 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-γ 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.
Toll样受体7（TLR7）与系统性红斑狼疮（SLE）的发生发展相关，但其潜在机制尚未完全明确。虽然已知Toll样受体（TLR）可激活I型干扰素（T1IFN）信号通路，但T1IFN和干扰素-γ（IFN-γ）信号通路在TLR7介导的抗体形成细胞（AFC）和生发中心（GC）反应的差异调节以及SLE发生发展中的作用从未被直接研究过。在本研究中，我们利用SLE的TLR7诱导和TLR7过表达模型，报道了TLR7诱导的IFN-γ信号通路在促进AFC和GC反应、导致自身反应性B细胞产生及SLE发生发展方面一个此前未被认识到的不可或缺的作用。相比之下，T1IFN信号通路在这些小鼠的自身免疫反应和疾病进程中仅起适度作用。用TLR7配体咪喹莫特处理IFN-γ报告基因小鼠表明，包括滤泡辅助性T（Tfh）细胞在内的CD4效应T细胞是TLR7诱导的IFN-γ的主要产生者。对咪喹莫特处理的、对IFN-γ受体充足和缺乏的自身免疫易感B6.Sle1b小鼠脾脏组织进行转录组分析表明，TLR7诱导的IFN-γ激活多种信号通路以调节TLR7促进的SLE。在外周B细胞中条件性缺失该基因进一步证明，TLR7驱动的自身免疫性AFC、GC和Tfh反应以及SLE的发生发展依赖于B细胞中的IFN-γ信号通路。最后，我们展示了信号转导和转录激活因子1（STAT1）和T-bet在B细胞中对于TLR7驱动的GC、Tfh和浆细胞分化起关键的细胞内固有作用。总之，我们揭示了IFN-γ及其下游信号分子STAT1和T-bet在B细胞中对于促进TLR7驱动的AFC、GC和SLE发生发展具有非冗余作用，而T1IFN信号通路对这些过程起适度作用。
