| First Author | Domeier PP | Year | 2016 |
| Journal | J Exp Med | Volume | 213 |
| Issue | 5 | Pages | 715-32 |
| PubMed ID | 27069112 | Mgi Jnum | J:233319 |
| Mgi Id | MGI:5781255 | Doi | 10.1084/jem.20151722 |
| Citation | Domeier PP, et al. (2016) IFN-gamma receptor and STAT1 signaling in B cells are central to spontaneous germinal center formation and autoimmunity. J Exp Med 213(5):715-32 |
| abstractText | Spontaneously developed germinal centers (GCs [Spt-GCs]) harbor autoreactive B cells that generate somatically mutated and class-switched pathogenic autoantibodies (auto-Abs) to promote autoimmunity. However, the mechanisms that regulate Spt-GC development are not clear. In this study, we report that B cell-intrinsic IFN-gamma receptor (IFN-gammaR) and STAT1 signaling are required for Spt-GC and follicular T helper cell (Tfh cell) development. We further demonstrate that IFN-gammaR and STAT1 signaling control Spt-GC and Tfh cell formation by driving T-bet expression and IFN-gamma production by B cells. Global or B cell-specific IFN-gammaR deficiency in autoimmune B6.Sle1b mice leads to significantly reduced Spt-GC and Tfh cell responses, resulting in diminished antinuclear Ab reactivity and IgG2c and IgG2b auto-Ab titers compared with B6.Sle1b mice. Additionally, we observed that the proliferation and differentiation of DNA-reactive B cells into a GC B cell phenotype require B cell-intrinsic IFN-gammaR signaling, suggesting that IFN-gammaR signaling regulates GC B cell tolerance to nuclear self-antigens. The IFN-gammaR deficiency, however, does not affect GC, Tfh cell, or Ab responses against T cell-dependent foreign antigens, indicating that IFN-gammaR signaling regulates autoimmune, but not the foreign antigen-driven, GC and Tfh cell responses. Together, our data define a novel B cell-intrinsic IFN-gammaR signaling pathway specific to Spt-GC development and autoimmunity. This novel pathway can be targeted for future pharmacological intervention to treat systemic lupus erythematosus. |
