BANK1 Controls IgG Production Through TLR7-Dependent STAT1 Activation in a Lupus Model

The purpose of our study was to investigate the effects of the adaptor Bank1 in TLR7 signaling using the B6. Sle1.yaa mouse, a lupus model that develops disease through exacerbated TLR7 expression. Crosses of B6. Sle1.yaa with Bank1 −/− mice maintained several B and myeloid cell phenotypes close to normal levels in wild-type mice. Most striking was the reduction in total serum IgG antibodies, but not of IgM, and reduced serum levels of autoantibodies, IL-6, and BAFF. Bank1 deficiency did modify frequencies of MZ B cells and splenic B cells, as well as expression of CXCR4 by follicular helper T cells. Bank1 deficiency did not modify frequencies of germinal center B cells or plasma cells or clinical disease outcomes. Purified B cells from B6 .Sle1.yaa.Bank1−/− mice had lost strong induction of Ifnb , Ifna4, Irf1, 7, 9 , Aicda and Stat1 gene expression following TLR7 agonist stimulation, compared with B6. Sle1.yaa mice. Interestingly, phosphorylation of Tyr701, but not of Ser727 of STAT1, was impaired in splenic B cells from B6 .Sle1.yaa.Bank1−/− mice, as was the nuclear translocation of IRF7 in response to TLR7 agonist stimulation. Further, Bank1 deficiency in B6 .Sle1.yaa mice reduced the production of IgG2c after in vitro TLR7 agonist stimulation. Our results demonstrate that Bank1 controls TLR7-mediated type I interferon production, leading to positive feedback loop on IFNAR and IFN I-mediated gene expression, including Tlr7 gene. Combined with the control of the nuclear translocation of IRF7, and the modulation of transcription and STAT1 phosphorylation, Bank1 contributes to IgG production during development of autoimmune disease.