Phosphodiesterases as Targets for Modulating T-Cell Responses
Phosphodiesterases as Targets for Modulating T-Cell Responses
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DOI：
10.1007/978-3-642-17969-3_15
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发表时间：
2011-01-01
期刊：
影响因子：
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通讯作者：
Tasken, Kjetil
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文献类型：
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作者：
Bjorgo, Elisa;Moltu, Kristine;Tasken, Kjetil
cAMP-蛋白激酶A（PKA）信号通路强烈参与免疫应答的调节和调节，并且cAMP是T细胞活化的最有效和最急性的抑制剂。因此，细胞中的cAMP水平必须严格调节。环腺苷酸特异性磷酸二酯酶（PDE）提供了降解细胞中cAMP的唯一机制，从而作为信号传导的关键调节因子发挥作用。为了获得具有最佳细胞因子产生和T细胞增殖的完全免疫应答，需要T细胞受体（TCR）和CD 28受体两者的连接。然而，TCR在原代T细胞中的参与之后是脂筏中的快速cAMP产生和抑制近端T细胞信号传导的cAMP PKA-Csk途径的激活。相反，TCR/CD 28共刺激导致PDE 4/β-affestin复合物以磷脂酰肌醇3-激酶（PI 3 K）依赖性方式募集到筏，导致cAMP水平下调。因此，PKA和PDE 4的活性似乎对于TCR诱导的信号传导和T细胞功能的调节是重要的。选择性抑制剂的使用已经揭示PDE是具有炎性组分的几种疾病中的重要药物靶标，其中免疫功能是重要的，例如哮喘、慢性阻塞性肺病（COPD）、心血管疾病和神经系统疾病。PDE也是移植后免疫抑制和调节免疫应答的有趣药物靶标。
The cAMP-protein kinase A (PKA) signaling pathway is strongly involved in the regulation and modulation of immune responses, and cAMP is the most potent and acute inhibitor of T-cell activation. Thus, cAMP levels in the cell must be tightly regulated. Cyclic AMP-specific phosphodiesterases (PDEs) provide the only mechanism for degrading cAMP in cells, thereby functioning as key regulators of signaling. To obtain a complete immune response with optimal cytokine production and T-cell proliferation, ligation of both the T-cell receptor (TCR) and the CD28 receptor is required. However, engagement of the TCR in primary T cells is followed by rapid cAMP production in lipid rafts and activation of the cAMP PKA-Csk pathway inhibiting proximal T-cell signaling. In contrast, TCR/CD28 costimulation leads to the recruitment of a PDE4/beta-affestin complex to rafts in a phosphatidylinositol 3-kinase (PI3K)-dependent manner, resulting in the downregulation of cAMP levels. Thus, the activities of both PKA and PDE4 seem to be important for regulation of TCR-induced signaling and T-cell function. The use of selective inhibitors has revealed that PDEs are important drug targets in several diseases with an inflammatory component where immune function is important such as asthma, chronic obstructive pulmonary disease (COPD), cardiovascular diseases, and neurological disorders. PDEs are also interesting drug targets in immunosuppression following transplantation and for modulation of immune responses.