| First Author | Wallace CH | Year | 2018 |
| Journal | JCI Insight | Volume | 3 |
| Issue | 7 | PubMed ID | 29618665 |
| Mgi Jnum | J:279197 | Mgi Id | MGI:6356670 |
| Doi | 10.1172/jci.insight.99863 | Citation | Wallace CH, et al. (2018) B lymphocytes confer immune tolerance via cell surface GARP-TGF-beta complex. JCI Insight 3(7) |
| abstractText | GARP, a cell surface docking receptor for binding and activating latent TGF-beta, is highly expressed by platelets and activated Tregs. While GARP is implicated in immune invasion in cancer, the roles of the GARP-TGF-beta axis in systemic autoimmune diseases are unknown. Although B cells do not express GARP at baseline, we found that the GARP-TGF-beta complex is induced on activated human and mouse B cells by ligands for multiple TLRs, including TLR4, TLR7, and TLR9. GARP overexpression on B cells inhibited their proliferation, induced IgA class-switching, and dampened T cell-independent antibody production. In contrast, B cell-specific deletion of GARP-encoding gene Lrrc32 in mice led to development of systemic autoimmune diseases spontaneously as well as worsening of pristane-induced lupus-like disease. Canonical TGF-beta signaling more readily upregulates GARP in Peyer patch B cells than in splenic B cells. Furthermore, we demonstrated that B cells are required for the induction of oral tolerance of T cell-dependent antigens via GARP. Our studies reveal for the first time to our knowledge that cell surface GARP-TGF-beta is an important checkpoint for regulating B cell peripheral tolerance, highlighting a mechanism of autoimmune disease pathogenesis. |
