Departments of Pathology, Immunology and Otolaryngology, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA
Eur J Immunol. 2012 Jul;42(7):1876-85. doi: 10.1002/eji.201142347. Epub 2012 Jun 18.
Human CD4(+) CD39(+) regulatory T (Treg) cells hydrolyze exogenous adenosine triphosphate (ATP) and participate in immunosuppressive adenosine production. They contain two T-cell subsets whose role in mediating suppression is not understood. Frequencies of both CD4(+) CD39(+) subsets were evaluated in peripheral blood lymphocytes of 57 cancer patients and in tumor infiltrating lymphocytes (TILs) of 6 patients. CD4(+) CD39(+) and CD4(+) CD39(neg) T cells isolated using immunobeads and cell sorting were cultured under various conditions. Their conversion into CD39(+) FOXP3(+) CD25(+) or CD39(+) FOX(neg) CD25(neg) cells was monitored by multiparameter flow cytometry. Hydrolysis of exogenous ATP was measured in luminescence assays. Two CD4(+) CD39(+) cell subsets differing in expression of CD25, FOXP3, CTLA-4, CD121a, PD-1, latency associated peptide (LAP), glycoprotein A repetitions predominant (GARP), and the cytokine profile accumulated with equal frequencies in the blood and tumor tissues of cancer patients. The frequency of both subsets was significantly increased in cancer. CD39 expression levels correlated with the subsets' ability to hydrolyze ATP. Conventional CD4(+) CD39(neg) T cells incubated with IL-2 + TGF-β expanded to generate CD4(+) CD39(+) FOXP3(+) Treg cells, while CD4(+) CD39(+) FOXP3(neg) CD25(neg) subset cells stimulated via the TCR and IL-2 converted to FOXP3(+) CTLA4(+) CD25(+) TGF-β-expressing Treg cells. Among CD4(+) CD39(+) Treg cells, the CD4(+) CD39(+) FOXP3(neg) CD25(neg) subset serves as a reservoir of cells able to convert to Treg cells upon activation by environmental signals.
人 CD4(+) CD39(+) 调节性 T（Treg）细胞水解外源性三磷酸腺苷（ATP）并参与免疫抑制腺苷的产生。它们包含两个 T 细胞亚群，其在介导抑制中的作用尚不清楚。评估了 57 例癌症患者外周血淋巴细胞和 6 例肿瘤浸润淋巴细胞（TIL）中 CD4(+) CD39(+) 两个亚群的频率。使用免疫珠和细胞分选分离 CD4(+) CD39(+) 和 CD4(+) CD39(neg) T 细胞，并在各种条件下培养。通过多参数流式细胞术监测其转化为 CD39(+) FOXP3(+) CD25(+) 或 CD39(+) FOX(neg) CD25(neg) 细胞。通过发光测定法测量外源性 ATP 的水解。在血液和肿瘤组织中，癌症患者中两种 CD4(+) CD39(+) 细胞亚群在表达 CD25、FOXP3、CTLA-4、CD121a、PD-1、潜伏相关肽（LAP）、糖蛋白 A 重复为主（GARP）和细胞因子谱方面存在差异，并且具有相同的频率。两种亚群的频率在癌症中均显著增加。CD39 表达水平与亚群水解 ATP 的能力相关。与 IL-2 + TGF-β 孵育的常规 CD4(+) CD39(neg) T 细胞扩增生成 CD4(+) CD39(+) FOXP3(+) Treg 细胞，而通过 TCR 和 IL-2 刺激的 CD4(+) CD39(+) FOXP3(neg) CD25(neg) 亚群细胞转化为 FOXP3(+) CTLA4(+) CD25(+) TGF-β 表达 Treg 细胞。在 CD4(+) CD39(+) Treg 细胞中，CD4(+) CD39(+) FOXP3(neg) CD25(neg) 亚群作为细胞库，能够在环境信号激活时转化为 Treg 细胞。
