The transmembrane protein GARP serves as a receptor for latent TGF-β, resulting in activation of this cytokine. GARP is expressed on the surface of Tregs, tumors, and platelets and has been implicated in cancer immune invasion. In this episode, Zihai Li and colleagues reveal that the GARP-TGF-β complex is present on activated, but not resting, human and murine B cells. Using multiple murine genetic models, the authors determined that this complex is essential for maintaining immune tolerance and for preventing autoimmune disease. These results support further exploration of B cell GARP as a therapeutic target and possible diagnostic tool.
GARP, a cell surface docking receptor for binding and activating latent TGF-β, is highly expressed by platelets and activated Tregs. While GARP is implicated in immune invasion in cancer, the roles of the GARP-TGF-β axis in systemic autoimmune diseases are unknown. Although B cells do not express GARP at baseline, we found that the GARP-TGF-β 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-β 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-β is an important checkpoint for regulating B cell peripheral tolerance, highlighting a mechanism of autoimmune disease pathogenesis.
Caroline H. Wallace, Bill X. Wu, Mohammad Salem, Ephraim A. Ansa-Addo, Alessandra Metelli, Shaoli Sun, Gary Gilkeson, Mark J. Shlomchik, Bei Liu, Zihai Li