Uraushihara Koji, Kanai Takanori, Ko Kwibeom, Totsuka Teruji, Makita Shin, Iiyama Ryoichi, Nakamura Tetsuya, Watanabe Mamoru
Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan.
J Immunol. 2003 Jul 15;171(2):708-16. doi: 10.4049/jimmunol.171.2.708.
CD4(+)CD25(+) regulatory T cells in normal animals are engaged in the maintenance of immunological self-tolerance and prevention of autoimmune disease. However, accumulating evidence suggests that a fraction of the peripheral CD4(+)CD25(-) T cell population also possesses regulatory activity in vivo. Recently, it has been shown glucocorticoid-induced TNFR family-related gene (GITR) is predominantly expressed on CD4(+)CD25(+) regulatory T cells. In this study, we show evidence that CD4(+)GITR(+) T cells, regardless of the CD25 expression, regulate the mucosal immune responses and intestinal inflammation. SCID mice restored with the CD4(+)GITR(-) T cell population developed wasting disease and severe chronic colitis. Cotransfer of CD4(+)GITR(+) population prevented the development of CD4(+)CD45RB(high) T cell-transferred colitis. Administration of anti-GITR mAb-induced chronic colitis in mice restored both CD45RB(high) and CD45RB(low) CD4(+) T cells. Interestingly, both CD4(+)CD25(+) and CD4(+)CD25(-) GITR(+) T cells prevented wasting disease and colitis. Furthermore, in vitro studies revealed that CD4(+)CD25(-)GITR(+) T cells as well as CD4(+)CD25(+)GITR(+) T cells expressed CTLA-4 intracellularly, showed anergic, suppressed T cell proliferation, and produced IL-10 and TGF-beta. These data suggest that GITR can be used as a specific marker for regulatory T cells controlling mucosal inflammation and also as a target for treatment of inflammatory bowel disease.
正常动物体内的CD4(+)CD25(+)调节性T细胞参与维持免疫自身耐受性并预防自身免疫性疾病。然而，越来越多的证据表明，外周CD4(+)CD25(-)T细胞群体中的一部分在体内也具有调节活性。最近，研究表明糖皮质激素诱导的TNFR家族相关基因（GITR）主要在CD4(+)CD25(+)调节性T细胞上表达。在本研究中，我们证明，无论CD25表达情况如何，CD4(+)GITR(+)T细胞均可调节黏膜免疫反应和肠道炎症。用CD4(+)GITR(-)T细胞群体重建的SCID小鼠出现消瘦病和严重的慢性结肠炎。共转移CD4(+)GITR(+)群体可预防CD4(+)CD45RB(high)T细胞转移所致的结肠炎。给予抗GITR单克隆抗体可在小鼠中诱导慢性结肠炎，这会使CD45RB(high)和CD45RB(low)CD4(+)T细胞均恢复。有趣的是，CD4(+)CD25(+)和CD4(+)CD25(-)GITR(+)T细胞均可预防消瘦病和结肠炎。此外，体外研究显示，CD4(+)CD25(-)GITR(+)T细胞以及CD4(+)CD25(+)GITR(+)T细胞在细胞内表达CTLA-4，表现为无反应性，抑制T细胞增殖，并产生IL-10和TGF-β。这些数据表明，GITR可作为控制黏膜炎症的调节性T细胞的特异性标志物，也可作为炎性肠病治疗的靶点。
