Zhou Q, Yan J, Putheti P, Wu Y, Sun X, Toxavidis V, Tigges J, Kassam N, Enjyoji K, Robson S C, Strom T B, Gao W
Department of Medicine, The Transplant Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Am J Transplant. 2009 Oct;9(10):2303-11. doi: 10.1111/j.1600-6143.2009.02777.x. Epub 2009 Jul 28.
Foxp3(+) regulatory T cells (Tregs) express both ectoenzymes CD39 and CD73, which in tandem hydrolyze pericellular ATP into adenosine, an immunoinhibitory molecule that contributes to Treg suppressive function. Using Foxp3GFP knockin mice, we noted that the mouse CD4(+)CD39(+) T-cell pool contains two roughly equal size Foxp3(+) and Foxp3(-) populations. While Foxp3(+)CD39(+) cells are CD73(bright) and are the bone fide Tregs, Foxp3(-)CD39(+) cells do not have suppressive activity and are CD44(+)CD62L(-)CD25(-)CD73(dim/-), exhibiting memory cell phenotype. Functionally, CD39 expression on memory and Treg cells confers protection against ATP-induced apoptosis. Compared with Foxp3(-)CD39(-) naïve T cells, Foxp3(-)CD39(+) cells freshly isolated from non-immunized mice express at rest significantly higher levels of mRNA for T-helper lineage-specific cytokines IFN-gamma (Th1), IL-4/IL-10 (Th2), IL-17A/F (Th17), as well as pro-inflammatory cytokines, and rapidly secrete these cytokines upon stimulation. Moreover, the presence of Foxp3(-)CD39(+) cells inhibits TGF-beta induction of Foxp3 in Foxp3(-)CD39(-) cells. Furthermore, when transferred in vivo, Foxp3(-)CD39(+) cells rejected MHC-mismatched skin allografts in a much faster tempo than Foxp3(-)CD39(-) cells. Thus, besides Tregs, CD39 is also expressed on pre-existing memory T cells of Th1-, Th2- and Th17-types with heightened alloreactivity.
叉头框蛋白3（Foxp3）阳性调节性T细胞（Tregs）表达胞外酶CD39和CD73，二者协同作用将细胞周围的三磷酸腺苷（ATP）水解为腺苷，腺苷是一种免疫抑制分子，有助于Treg的抑制功能。利用Foxp3绿色荧光蛋白（GFP）基因敲入小鼠，我们发现小鼠CD4阳性CD39阳性T细胞库包含两个大小大致相等的群体，即Foxp3阳性和Foxp3阴性群体。虽然Foxp3阳性CD39阳性细胞CD73高表达，是真正的Tregs，但Foxp3阴性CD39阳性细胞没有抑制活性，为CD44阳性CD62L阴性CD25阴性CD73低表达/不表达，表现出记忆细胞表型。在功能上，记忆细胞和Treg细胞上的CD39表达赋予细胞抵抗ATP诱导的凋亡的能力。与Foxp3阴性CD39阴性初始T细胞相比，从未免疫小鼠新鲜分离的Foxp3阴性CD39阳性细胞在静息状态下表达明显更高水平的辅助性T细胞谱系特异性细胞因子干扰素-γ（Th1）、白细胞介素-4/白细胞介素-10（Th2）、白细胞介素-17A/F（Th17）以及促炎细胞因子，并且在受到刺激后迅速分泌这些细胞因子。此外，Foxp3阴性CD39阳性细胞的存在会抑制Foxp3阴性CD39阴性细胞中转化生长因子-β（TGF-β）诱导的Foxp3表达。此外，当体内转移时，Foxp3阴性CD39阳性细胞排斥主要组织相容性复合体（MHC）不匹配皮肤同种异体移植物的速度比Foxp3阴性CD39阴性细胞快得多。因此，除了Tregs外，CD39也表达于具有增强同种异体反应性的Th1、Th2和Th17型的现存记忆T细胞上。
