Repression of Cyclic Adenosine Monophosphate Upregulation Disarms and Expands Human Regulatory T Cells
Repression of Cyclic Adenosine Monophosphate Upregulation Disarms and Expands Human Regulatory T Cells
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DOI：
10.4049/jimmunol.1102045
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发表时间：
2012-02-01
影响因子：
4.4
通讯作者：
Becker, Christian
中科院分区：
文献类型：
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作者：
Klein, Matthias;Vaeth, Martin;Becker, Christian
人调节性T细胞（Treg）介导的抑制的主要分子机制尚未阐明。我们在这项研究中表明，cAMP是人类Treg功能的关键调节因子。通过抑制腺苷酸环化酶活性抑制cAMP产生或通过cAMP降解磷酸二酯酶的异位表达增强cAMP降解大大降低了人Treg在体外和人源化小鼠模型中的体内抑制活性。值得注意的是，cAMP抑制还消除了人Treg的无能状态，同时伴有NFATc 1的核易位及其短亚型NFATc 1/alpha A的诱导。然而，在cAMP抑制下扩增的Treg不转化为效应T细胞，并且在增殖时恢复其无能状态和抑制活性。总之，这些发现揭示了cAMP途径作为Treg功能临床干预的有吸引力的靶标。免疫学杂志，2012，188：1091-1097。
The main molecular mechanism of human regulatory T cell (Treg)-mediated suppression has not been elucidated. We show in this study that cAMP represents a key regulator of human Treg function. Repression of cAMP production by inhibition of adenylate cyclase activity or augmentation of cAMP degradation through ectopic expression of a cAMP-degrading phosphodiesterase greatly reduces the suppressive activity of human Treg in vitro and in a humanized mouse model in vivo. Notably, cAMP repression additionally abrogates the anergic state of human Treg, accompanied by nuclear translocation of NFATc1 and induction of its short isoform NFATc1/alpha A. Treg expanded under cAMP repression, however, do not convert into effector T cells and regain their anergic state and suppressive activity upon proliferation. Together, these findings reveal the cAMP pathway as an attractive target for clinical intervention with Treg function. The Journal of Immunology, 2012, 188: 1091-1097.