B lymphocytes confer immune tolerance via cell surface GARP-TGF-ß complex.
JCI Insight
; 3(7)2018 04 05.
Article
en En
| MEDLINE
| ID: mdl-29618665
GARP, a cell surface docking receptor for binding and activating latent TGF-ß, is highly expressed by platelets and activated Tregs. While GARP is implicated in immune invasion in cancer, the roles of the GARP-TGF-ß axis in systemic autoimmune diseases are unknown. Although B cells do not express GARP at baseline, we found that the GARP-TGF-ß 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-ß 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-ß is an important checkpoint for regulating B cell peripheral tolerance, highlighting a mechanism of autoimmune disease pathogenesis.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Linfocitos B
/
Factor de Crecimiento Transformador beta
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Tolerancia Inmunológica
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Proteínas de la Membrana
Límite:
Animals
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Female
/
Humans
Idioma:
En
Revista:
JCI Insight
Año:
2018
Tipo del documento:
Article
Pais de publicación:
Estados Unidos