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JCI Insight. 2018 Apr 5;3(7). pii: 99863. doi: 10.1172/jci.insight.99863. eCollection 2018 Apr 5.

B lymphocytes confer immune tolerance via cell surface GARP-TGF-β complex.

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Department of Microbiology and Immunology.
Department of Pathology and Laboratory Medicine, and.
Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.
Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
First Affiliated Hospital, Zhengzhou University School of Medicine, Zhengzhou, China.


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.


Autoimmunity; B cells; Immunology; Lupus; Tolerance

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