Department of Microbiology and Immunology.
Department of Pathology and Laboratory Medicine, and.
JCI Insight. 2018 Apr 5;3(7). doi: 10.1172/jci.insight.99863.
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.
GARP 是一种细胞表面 docking 受体，可结合并激活潜伏的 TGF-β，在血小板和活化的 Tregs 中高度表达。虽然 GARP 被认为与癌症中的免疫浸润有关，但 GARP-TGF-β 轴在系统性自身免疫性疾病中的作用尚不清楚。尽管 B 细胞在基线时不表达 GARP，但我们发现，多种 TLR 的配体可诱导活化的人和鼠 B 细胞上的 GARP-TGF-β 复合物的形成，包括 TLR4、TLR7 和 TLR9。B 细胞上 GARP 的过表达抑制其增殖，诱导 IgA 类别转换，并抑制 T 细胞非依赖性抗体的产生。相比之下，在小鼠中特异性敲除 B 细胞中编码基因 Lrrc32 的 GARP 会导致自发性全身性自身免疫性疾病的发展以及对 pristane 诱导的狼疮样疾病的加重。经典的 TGF-β 信号更容易上调派尔集合淋巴结中的 GARP，而不是脾脏中的 B 细胞。此外，我们证明 B 细胞是通过 GARP 诱导 T 细胞依赖性抗原口服耐受所必需的。我们的研究首次揭示了细胞表面 GARP-TGF-β 是调节 B 细胞外周耐受的一个重要检查点，突出了自身免疫病发病机制的一种机制。
