Morra M, Zubiaur M, Terhorst C, Sancho J, Malavasi F
Department of Genetics, Biology and Medical Chemistry, and Postgraduate School of Clinical Pathology, University of Torino Medical School, Italy.
FASEB J. 1998 May;12(7):581-92. doi: 10.1096/fasebj.12.7.581.
One of the functions of surface CD38 is the induction of phosphorylation of discrete cytoplasmic substrates and mobilization of cytoplasmic calcium (Ca2+). The present work addresses the issue of whether the signaling mediated via CD38 operates through an independent pathway or, alternatively, is linked to the TCR/CD3 signaling machinery. We studied the signals elicited through CD38 by the specific agonistic IB4 monoclonal antibody (mAb) by monitoring the levels of cytoplasmic Ca2+ and the induced phenotypic and functional variations in T cell growth. IB4 mAb presented the unique ability to increase cytoplasmic Ca2+ levels, which correlated with the phosphorylation of the PLC-gamma1. These effects were blocked by phorbol 12-myristate 13-acetate (PMA) and were dependent on the presence of a functional TCR/CD3 surface complex, no effects being recorded on mutant Jurkat cells lacking part of the CD3 structures. CD38 signaling appeared to share with TCR/CD3 the ability to induce apoptotic cell death in Jurkat T cells, an event paralleled by specific up-regulation of the Fas molecule and inhibited by cyclosporin A. CD28, a costimulatory molecule, is synergized by increasing CD38-induced apoptotic cell death. The results indicate the existence of a strong functional interdependence between CD38 and TCR/CD3.
表面CD38的功能之一是诱导离散细胞质底物的磷酸化以及细胞质钙（Ca2+）的动员。目前的工作探讨了经由CD38介导的信号传导是通过独立途径发挥作用，还是与TCR/CD3信号传导机制相关联这一问题。我们通过监测细胞质Ca2+水平以及T细胞生长中诱导的表型和功能变化，研究了特异性激动性IB4单克隆抗体（mAb）通过CD38引发的信号。IB4 mAb具有独特的能力来提高细胞质Ca2+水平，这与PLC-γ1的磷酸化相关。这些效应被佛波醇12-肉豆蔻酸酯13-乙酸酯（PMA）阻断，并且依赖于功能性TCR/CD3表面复合物的存在，在缺乏部分CD3结构的突变Jurkat细胞上未记录到任何效应。CD38信号传导似乎与TCR/CD3共享在Jurkat T细胞中诱导凋亡性细胞死亡的能力，这一事件伴随着Fas分子的特异性上调，并被环孢素A抑制。共刺激分子CD28通过增强CD38诱导的凋亡性细胞死亡而产生协同作用。结果表明CD38与TCR/CD3之间存在强烈的功能相互依赖性。
