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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.

Author information

1
Department of Microbiology and Immunology.
2
Department of Pathology and Laboratory Medicine, and.
3
Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.
4
Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
5
First Affiliated Hospital, Zhengzhou University School of Medicine, Zhengzhou, China.

Abstract

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.

KEYWORDS:

Autoimmunity; B cells; Immunology; Lupus; Tolerance

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