Huang S, Apasov S, Koshiba M, Sitkovsky M
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1892, USA.
Blood. 1997 Aug 15;90(4):1600-10.
Accumulation of adenosine and of deoxyadenosine in the absence of adenosine deaminase activity (ADA) activity results in lymphocyte depletion and in severe combined immunodeficiency (ADA SCID), which is currently explained by direct cell death-causing effects of intracellular products of adenosine metabolism. We explored the alternative mechanisms of peripheral T-cell depletion as due to inhibition of T-cell expansion by extracellular adenosine-mediated signaling through purinergic receptors. The strong inhibition of the T-cell receptor (TCR)-triggered proliferation and of upregulation of interleukin-2 receptor alpha chain (CD25) molecules, but not the direct lymphotoxicity, were observed at low concentrations of extracellular adenosine. These effects of extracellular adenosine (Ado) are likely to be mediated by A2a receptor-mediated signaling rather than by intracellular toxicity of adenosine catabolites, because (1) poorly metabolized adenosine analogs cause the accumulation of cAMP and strong inhibition of TCR-triggered CD25 upregulation; (2) the A2a, but not the A1 or A3, receptors are the major expressed and functionally coupled adenosine receptors in mouse peripheral T and B lymphocytes, and the adenosine-induced cAMP accumulation in lymphocytes correlates with the expression of A2a receptors; (3) the specific agonist of A2a receptor, CGS21680, induces increases in [cAMP]i in lymphocytes, whereas the specific antagonist of A2a receptor, CSC, inhibits the effects of Ado and CGS21680; and (4) the increases in [cAMP]i mimic the adenosine-induced inhibition of TCR-triggered CD25 upregulation and splenocyte proliferation. These studies suggest the possible role of adenosine receptors in the regulation of lymphocyte expansion and point to the downregulation of A2a purinergic receptors on T cells as a potentially attractive pharmacologic target.
在缺乏腺苷脱氨酶（ADA）活性的情况下，腺苷和脱氧腺苷的积累会导致淋巴细胞耗竭和严重联合免疫缺陷（ADA SCID），目前认为这是由腺苷代谢的细胞内产物直接导致细胞死亡的作用所解释的。我们探索了外周T细胞耗竭的替代机制，即细胞外腺苷通过嘌呤能受体介导的信号传导抑制T细胞扩增。在低浓度的细胞外腺苷下，观察到对T细胞受体（TCR）触发的增殖和白细胞介素-2受体α链（CD25）分子上调的强烈抑制，但未观察到直接的淋巴细胞毒性。细胞外腺苷（Ado）的这些作用可能是由A2a受体介导的信号传导介导的，而不是由腺苷分解代谢产物的细胞内毒性介导的，因为：（1）代谢不良的腺苷类似物会导致cAMP积累并强烈抑制TCR触发的CD25上调；（2）A2a受体而非A1或A3受体是小鼠外周T和B淋巴细胞中主要表达且功能偶联的腺苷受体，并且腺苷诱导的淋巴细胞中cAMP积累与A2a受体的表达相关；（3）A2a受体的特异性激动剂CGS21680可诱导淋巴细胞中[cAMP]i增加，而A2a受体的特异性拮抗剂CSC可抑制Ado和CGS21680的作用；（4）[cAMP]i的增加模拟了腺苷诱导的对TCR触发的CD25上调和脾细胞增殖的抑制。这些研究表明腺苷受体在淋巴细胞扩增调节中的可能作用，并指出T细胞上A2a嘌呤能受体的下调作为潜在有吸引力的药理学靶点。
