Human follicular lymphoma CD39+-infiltrating T cells contribute to adenosine-mediated T cell hyporesponsiveness.
Human follicular lymphoma CD39+-infiltrating T cells contribute to adenosine-mediated T cell hyporesponsiveness.
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DOI：
10.4049/jimmunol.0900475
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发表时间：
2009-11-15
期刊：
影响因子：
--
通讯作者：
Bernstein SH
中科院分区：
文献类型：
--
作者：
Hilchey SP;Kobie JJ;Cochran MR;Secor-Socha S;Wang JC;Hyrien O;Burack WR;Mosmann TR;Quataert SA;Bernstein SH
我们以前的工作已经证明，人类滤泡性淋巴瘤(FL)浸润性T细胞是无能的，部分原因是调节性T细胞的抑制。在这项研究中，我们发现细胞周围的腺苷与T细胞相关的G蛋白偶联的A2A/B腺苷受体(AR)相互作用，与FL T细胞低反应性有关。在一组FL患者样本中，与没有抑制剂的患者相比，用特定的A2A/B AR拮抗剂处理淋巴结单核细胞(LNMC)后，抗CD3/CD28Ab刺激的干扰素-γ或IL-2的分泌增加。相反，A1受体拮抗剂的治疗对细胞因子的分泌没有影响。由于从细胞周三磷酸腺苷产生腺苷的速率限制步骤是胞外ATPase CD39，我们接下来证明使用抑制剂ARL 67156抑制CD39活性部分克服了T细胞在部分患者样本中的低反应性。LNMC的表型特征显示表达CD39的CD4+和CD8+T细胞在FL中的表达高于在正常或反应性结节或正常外周血中的表达。30%的FL CD4+CD39+T细胞共表达CD25High和FOXP3(与调节性T细胞一致)。最后，FL或正常LNMC在体外以剂量和时间依赖的方式降解ATP，其消耗速率与CD39+T细胞的浸润程度有关。综上所述，这些结果支持了这样的发现：在人类肿瘤中，三磷酸腺苷-电子核糖核酸酶-腺苷系统介导T细胞无能。此外，这些研究表明，A2A/B受体和CD39是加强癌症免疫治疗的新的药理靶点。
Our previous work has demonstrated that human follicular lymphoma (FL) infiltrating T cells are anergic, in part due to suppression by regulatory T cells. In this study, we identify pericellular adenosine, interacting with T cell-associated G protein-coupled A2A/B adenosine receptors (AR), as contributing to FL T cell hyporesponsiveness. In a subset of FL patient samples, treatment of lymph node mononuclear cells (LNMC) with specific A2A/B AR antagonists results in an increase in IFN-γ or IL-2 secretion upon anti-CD3/CD28 Ab stimulation, as compared with that seen without inhibitors. In contrast, treatment with an A1 AR antagonist had no effect on cytokine secretion. As the rate limiting step for adenosine generation from pericellular ATP is the ecto-ATPase CD39, we next show that inhibition of CD39 activity using the inhibitor ARL 67156 partially overcomes T cell hyporesponsiveness in a subset of patient samples. Phenotypic characterization of LNMC demonstrates populations of CD39-expressing CD4+ and CD8+ T cells, which are overrepresented in FL as compared with that seen in normal or reactive nodes, or normal peripheral blood. Thirty percent of the FL CD4+CD39+ T cells coexpress CD25high and FOXP3 (consistent with regulatory T cells). Finally, FL or normal LNMC hydrolyze ATP in vitro, in a dose- and time-dependent fashion, with the rate of ATP consumption being associated with the degree of CD39+ T cell infiltration. Together, these results support the finding that the ATP-ectonucleotidase-adenosine system mediates T cell anergy in a human tumor. In addition, these studies suggest that the A2A/B AR as well as CD39 are novel pharmacological targets for augmenting cancer immunotherapy.
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DOI：
10.1073/pnas.0605251103
发表时间：
2006-08-29
影响因子：
11.1
作者：
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DOI：
10.1073/pnas.87.21.8267
发表时间：
1990-11-01
影响因子：
11.1
作者：
FILIPPINI, A;TAFFS, RE;SITKOVSKY, MV
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