Translational Gastroenterology Unit, Experimental Medicine Division, Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
Mucosal Immunol. 2013 Mar;6(2):324-34. doi: 10.1038/mi.2012.75. Epub 2012 Aug 22.
Thymic induction of CD4(+)Foxp3(+) regulatory T (Treg) cells relies on CD28 costimulation and high-affinity T-cell receptor (TCR) signals, whereas Foxp3 (forkhead box P3) induction on activated peripheral CD4(+) T cells is inhibited by these signals. Accordingly, the inhibitory molecule CTLA-4 (cytotoxic T-lymphocyte antigen 4) promoted, but was not essential for CD4(+) T-cell Foxp3 induction in vitro. We show that CTLA-4-deficient cells are equivalent to wild-type cells in the thymic induction of Foxp3 and maintenance of Foxp3 populations in the spleen and mesenteric lymph nodes, but their accumulation in the colon, where Treg cells specific for commensal bacteria accumulate, is impaired. In a T cell-transfer model of colitis, the two known CTLA-4 ligands, B7-1 and B7-2, had largely redundant roles in inducing inflammation and promoting Treg cell function. However, B7-2 proved more efficient than B7-1 in inducing Foxp3 in vitro and in vivo. Our data reveal an unappreciated role for CTLA-4 in establishing the Foxp3(+) compartment in the intestine.
胸腺中 CD4(+)Foxp3(+)调节性 T (Treg)细胞的诱导依赖于 CD28 共刺激和高亲和力 T 细胞受体 (TCR)信号，而 Foxp3（叉头框 P3）在激活的外周 CD4(+)T 细胞上的诱导则受到这些信号的抑制。因此，抑制分子 CTLA-4（细胞毒性 T 淋巴细胞抗原 4）促进但不是 CD4(+)T 细胞 Foxp3 体外诱导所必需的。我们表明，CTLA-4 缺陷细胞在胸腺中诱导 Foxp3 和维持脾脏和肠系膜淋巴结中的 Foxp3 群体方面与野生型细胞相当，但它们在结肠中的积累（Treg 细胞特异性针对共生菌的积累）受损。在结肠炎的 T 细胞转移模型中，两种已知的 CTLA-4 配体 B7-1 和 B7-2 在诱导炎症和促进 Treg 细胞功能方面具有很大的冗余作用。然而，B7-2 在体外和体内诱导 Foxp3 的效率均高于 B7-1。我们的数据揭示了 CTLA-4 在建立肠道中 Foxp3(+)隔室中的未被重视的作用。
