Reciprocal regulation of germinal center and regulatory B cell responses by IFNγ receptor-STAT1 signaling in TLR7 mediated autoimmunity

Abstract

Abstract Toll like receptor 7 (TLR7) plays a critical role in systemic autoimmunity. The mechanisms that fine-tune germinal center versus regulatory B cell response in TLR7 mediated autoimmunity remain unclear. Regulatory B cells that produce IL-10 (B10 cells) negatively regulate autoimmunity and infections. We report that TLR7 deficiency in non-autoimmune B6 and autoimmune prone B6.Sle1b mice showed increased IL-10 producing B10 cells. In contrast, B6.Yaa and B6.Sle1b.Yaa mice expressing an extra copy of TLR7 in the Yaa locus showed decreased percentage of B10 cells. TLR7 deficiency in B cells inhibited whereas an extra copy of TLR7 enhanced proliferation and cytokine expression of cocultured antigen specific CD4 T cells. Interestingly, B10 cells displayed highest IFNγR expression compared to other subsets of T and B cells. Whereas B6.Sle1b.Yaa mice lacked B10 cells and marginal zone compartment (MZ), B6.Sle1b.Yaa mice deficient in IFNγR (B6.Sle1b.Yaa/IFNγR−/−) restored these populations. Further, B6.Sle1b.Yaa/IFNγR−/− mice showed diminished spontaneous germinal center (Spt-GC) and serum autoantibody responses, and renal pathology compared to B6.Sle1b.Yaa control mice. Similar results were observed when B6.Sle1b and B6.Sle1b.IFNγR−/− mice were treated with TLR7 ligand, imiquimod. B10 and GC B cells exhibited higher STAT1 and T-bet expression than follicular B cells. Mice deficient in STAT1 and T-bet had significantly reduced GC and IgG2c Ab responses while retained intact B10 and MZ compartments upon imiquimod treatment, contrary to what was observed in wild type mice. Together, these data define the critical differential role of IFNγR, STAT1, and T-bet in GC B cell and B10 cell development in TLR7 mediated autoimmunity.