1Program of Developmental Immunology, Department of Pediatrics, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
J Clin Invest. 2010 Dec;120(12):4445-52. doi: 10.1172/JCI43796. Epub 2010 Nov 22.
Th17 cells are a distinct lineage of T helper cells that protect the body from bacterial and fungal infection. However, Th17 cells also contribute to inflammatory and autoimmune disorders such as multiple sclerosis. Th17 cell generation requires exposure of naive T cells to the cytokine TGF-β in combination with proinflammatory cytokines. Here we show that differentiation of Th17 cells is also critically dependent on αv integrins. In mice, lack of integrin αv in the immune system resulted in loss of Th17 cells in the intestine and lymphoid tissues. It also led to protection from experimental autoimmune encephalomyelitis (EAE). Further analysis indicated that αv integrins on DCs activated latent TGF-β during T cell stimulation and thereby promoted differentiation of Th17 cells. Furthermore, pharmacologic inhibition of αv integrins using cyclic RGD peptides blocked TGF-β activation and Th17 cell generation in vitro and protected mice from EAE. These data demonstrate that activation of TGF-β by αv-expressing myeloid cells may be a critical step in the generation of Th17 cells and suggest that αv integrins could be therapeutic targets in autoimmune disease.
Th17 细胞是一类特殊的辅助性 T 细胞，能够帮助人体抵御细菌和真菌感染。然而，Th17 细胞也会引发炎症和自身免疫性疾病，如多发性硬化症。Th17 细胞的产生需要幼稚 T 细胞暴露于 TGF-β 细胞因子，并与促炎细胞因子结合。在这里，我们发现 Th17 细胞的分化也严重依赖于αv 整合素。在小鼠中，免疫系统缺乏整合素 αv 会导致肠道和淋巴组织中 Th17 细胞的缺失，也会预防实验性自身免疫性脑脊髓炎（EAE）。进一步的分析表明，树突状细胞（DCs）上的 αv 整合素在 T 细胞刺激过程中激活潜伏的 TGF-β，从而促进 Th17 细胞的分化。此外，使用环状 RGD 肽抑制 αv 整合素可阻断 TGF-β 的激活和 Th17 细胞的体外生成，并保护小鼠免受 EAE 的侵害。这些数据表明，αv 表达的髓样细胞激活 TGF-β 可能是 Th17 细胞产生的关键步骤，并提示 αv 整合素可能成为自身免疫性疾病的治疗靶点。
