Memory of extracellular adenosine A(2A) purinergic receptor-mediated signaling in murine T cells
Memory of extracellular adenosine A(2A) purinergic receptor-mediated signaling in murine T cells
复制标题
DOI：
10.1074/jbc.272.41.25881
复制
发表时间：
1997-10-10
影响因子：
4.8
通讯作者：
Sitkovsky, MV
中科院分区：
文献类型：
--
作者：
Koshiba, M;Kojima, H;Sitkovsky, MV
细胞外和细胞内的腺苷(ADO)在低氧条件下或在没有腺苷脱氨酶的情况下积聚会导致淋巴细胞耗竭和严重的联合免疫缺陷，目前解释这一现象的原因是腺苷代谢产物在细胞内的直接淋巴毒性。为了支持另一种“信号传递”机制，我们发现细胞外Ado(ExtAdo)抑制了所有被测试的T细胞受体(TCR)触发的T淋巴细胞的效应功能，包括TCR触发的细胞毒性T淋巴细胞中Fast mRNA的上调。在ADO暴露的T细胞中，TCR触发的生长抑制被取消，从而提供了有力的证据来反对ADO的细胞内淋巴毒性(并支持该信号模型)。短暂的ADO暴露足以观察到TCR触发的效应器功能的抑制。T细胞对extAdo的“记忆”可以用cAMP的持续增加来解释。A(2A)腺苷受体选择性激动剂(CGS21680)和拮抗剂(ZM241385)用于功能分析，不同类型腺苷受体的cDNA探针用于Northern印迹研究。A(2A)受体被认为是T细胞中主要表达的G(S)偶联腺苷受体亚型，A(2A)受体与TCR之间双向串扰的证明支持了A(2A)受体在腺苷脱氨酶缺乏和实体瘤等低氧条件下介导的体内免疫抑制机制中的可能作用。
Accumulation of extracellular and intracellular adenosine (Ado) under hypoxic conditions or in the absence of adenosine deaminase results in lymphocyte depletion and in severe combined immunodeficiency, which are currently explained by direct intracellular lymphotoxicity of Ado metabolites. In support of the alternative, ''signaling'' mechanism, we show that extracellular Ado (extAdo) suppresses all tested T cell receptor (TCR)triggered effector functions of T Lymphocytes including the TCR-triggered Fast mRNA up-regulation in cytotoxic T lymphocytes. Strong evidence against the intracellular lymphotoxicity of Ado (and in support of the signaling model) is provided by abrogation of TCR-triggered growth inhibition in Ado exposed T cells. The brief exposure to Ado was sufficient to observe inhibition of TCR-triggered effector functions. The ''memory'' of T cells to exposure to extAdo is best explained by sustained increases in cAMP. Selective agonist (CGS21680) and antagonist (ZM241385) of A(2A) adenosine receptor were used in functional assays and cDNA probes for different sybtypes of adenosine receptors were used in Northern blot studies. A(2A) receptors are identified as the predominantly expressed subtype of G(s)-coupled Ado receptors in T cells, The demonstration of cross-talk between the A(2A) receptors and TCR in both directions support the possible role of A(2A) receptors in mechanisms of extAdo-mediated immunosuppression in vivo under adenosine deaminase deficiency and hypoxic conditions in, e.g., solid tumors.