BANK1 Regulates IgG Production in a Lupus Model by Controlling TLR7-Dependent STAT1 Activation

<div><p>The purpose of our study was to investigate the effects of the adaptor Bank1 in TLR7 signaling using the B6.<i>Sle1</i>.<i>yaa</i> mouse, a lupus model that develops disease through exacerbated TLR7 expression. Crosses of B6.<i>Sle1</i>.<i>yaa</i> with <i>Bank1</i>^<i>-/-</i> mice maintained several B and myeloid cell phenotypes close to normal wild-type levels. Most striking was the reduction in total serum IgG antibodies, but not of IgM, and reduced serum levels of autoantibodies, IL-6, and BAFF. <i>Bank1</i> deficiency did modify numbers of MZ B cells and total B cell numbers, as well as expression of CXCR4 by follicular helper T cells. Other T cell changes were not observed. <i>Bank1</i> deficiency did not modify numbers of germinal center B cells or plasma cells or clinical disease outcomes. Purified B cells from <i>Bank1</i> deficient mice had strongly reduced <i>Ifnb</i>, <i>Ifna4</i>, <i>Irf7</i>, <i>Aicda</i> and <i>Stat1</i> gene expression following TLR7 agonist stimulation. Interestingly, phosphorylation of Tyr701, but not of Ser727 of STAT1, was impaired in splenic B cells from <i>B6</i>.<i>Sle1</i>.<i>yaa</i>.<i>Bank1-/-</i> mice, as was the nuclear translocation of IRF7 in response to TLR7 agonist stimulation. Further, <i>Bank1</i> deficiency in B6.<i>Sle1</i>.<i>yaa</i> mice reduced the production of IgG2c after <i>in vitro</i> TLR7 agonist stimulation. Our results demonstrate that <i>Bank1</i> controls TLR7-mediated type I interferon production. Combined with the control of the nuclear translocation of IRF7, the modulation of STAT1 transcription and phosphorylation, <i>Bank1</i> contributes to IgG production during development of autoimmune disease.</p>