Type II but not type I IFN signaling is indispensable for TLR7-promoted development of autoreactive B cells and systemic autoimmunity

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-g 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-g 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-g reporter mice show that CD4⁺ effector T cells including follicular helper T (Tfh) cells are the major producers of TLR7-induced IFN-g. Transcriptomic analysis of splenic tissues from imiquimod-treated autoimmune-prone B6.Sle1b mice sufficient and deficient for IFN-gR indicates that TLR7-induced IFN-g 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-g 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-g 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. The Journal of Immunology, 2020, 204: 796-809.