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

Sathi Babu Chodisetti, Adam J. Fike, Phillip P. Domeier, Harinder Singh, Nicholas M. Choi, Chelsea Corradetti, Yuka Imamura Kawasawa, Timothy Cooper, Roberto Caricchio, Ziaur S.M. Rahman

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)796-809
Number of pages14
JournalJournal of Immunology
Volume204
Issue number4
DOIs
StatePublished - Feb 15 2020

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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