Laboratory of Immunology, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Eur J Immunol. 2013 Sep;43(9):2421-9. doi: 10.1002/eji.201343451. Epub 2013 Jul 3.
Treg cells express high levels of the glucocorticoid-induced tumor necrosis factor-related receptor (GITR), while resting conventional T (Tconv) cells express low levels that are increased upon activation. Manipulation of GITR/GITR-Ligand (GITR-L) interactions results in enhancement of immune responses, but it remains unclear whether this enhancement is secondary to costimulation of Tconv cells or to reversal of Treg-cell-mediated suppression. Here, we used a nondepleting Fc-GITR-L and combinations of WT and GITR KO Treg cells and Tconv cells to reexamine the effects of GITR stimulation on each subpopulation in both unmanipulated mice and mice with inflammatory bowel disease. Treatment of mice with Fc-GITR-L resulted in significant expansion of Treg cells and a modest expansion of Tconv cells. When RAG KO mice were reconstituted with Tconv cells alone, GITR-L resulted in Tconv-cell expansion and severe inflammatory bowel disease. The protective effect of Treg cells was lost in the presence of Fc-GITR-L, secondary to death of the Treg cells. When RAG KO mice were reconstituted with Treg cells alone, the transferred cells expanded normally, and Fc-GITR-L treatment resulted in a loss of Foxp3 expression, but the ex-Treg cells did not cause any pathology. The effects of GITR activation are complex and depend on the host environment and the activation state of the Treg cells and T effector cells.
调节性 T（Treg）细胞表达高水平的糖皮质激素诱导的肿瘤坏死因子相关受体（GITR），而静息的常规 T（Tconv）细胞表达低水平的 GITR，其在激活后增加。GITR/GITR 配体（GITR-L）相互作用的操纵导致免疫反应增强，但尚不清楚这种增强是继发于 Tconv 细胞的共刺激还是 Treg 细胞介导的抑制的逆转。在这里，我们使用非耗竭性 Fc-GITR-L 以及 WT 和 GITR KO Treg 细胞和 Tconv 细胞的组合，重新检查 GITR 刺激对未处理的小鼠和炎症性肠病小鼠中每种亚群的影响。Fc-GITR-L 治疗导致 Treg 细胞的显著扩增和 Tconv 细胞的适度扩增。当 RAG KO 小鼠用 Tconv 细胞单独重建时，GITR-L 导致 Tconv 细胞扩增和严重的炎症性肠病。在 Fc-GITR-L 存在下，Treg 细胞的保护作用丧失，这是由于 Treg 细胞死亡所致。当 RAG KO 小鼠用 Treg 细胞单独重建时，转移细胞正常扩增，Fc-GITR-L 治疗导致 Foxp3 表达丧失，但 ex-Treg 细胞不会引起任何病理。GITR 激活的作用是复杂的，取决于宿主环境以及 Treg 细胞和 T 效应细胞的激活状态。
