Type II but Not Type I IFN Signaling Is Indispensable for TLR7-Promoted Development of Autoreactive B Cells and Systemic Autoimmunity

• Published in: The Journal of immunology (1950) 2020-02, Vol.204 (4), p.796-809
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Animals; Autoimmunity - immunology; B-Lymphocytes - immunology; Germinal Center - immunology; Interferon Type I; Interferon-gamma - immunology; Lupus Erythematosus, Systemic - immunology; Lymphocyte Activation - immunology; Membrane Glycoproteins - immunology; Mice; Signal Transduction - immunology; Toll-Like Receptor 7 - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1901175

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.