Wang Hongyan, Wei Bin, Bismuth Georges, Rudd Christopher E
Cell Signaling Section, Department of Pathology, Tennis Court Road, University of Cambridge, Cambridge CB2 1QP, United Kingdom.
Proc Natl Acad Sci U S A. 2009 Jul 28;106(30):12436-41. doi: 10.1073/pnas.0900510106. Epub 2009 Jul 15.
Although adaptor ADAP (FYB) and its binding to SLP-76 has been implicated in TcR-induced "inside-out" signaling for LFA-1 activation in T cells, little is known regarding its role in LFA-1-mediated "outside-in" signaling. In this study, we demonstrate that ADAP and SLP-76-ADAP binding are coupled to LFA-1 costimulation of IL-2 production, F-actin clustering, cell polarization, and T cell motility. LFA-1 enhancement of anti-CD3-induced IL-2 production was completely dependent on SLP-76-ADAP binding. Further, anti-CD3 was found to require CD11a ligation by antibody or ICAM1 to cause T cell polarization. ADAP augmented this polarization induced by anti-CD3/CD11a, but not by anti-CD3 alone. ADAP expression with LFA-1 ligation alone was sufficient to polarize T cells directly and to increase T cell motility whereas the loss of ADAP in ADAP-/- primary T cells reduced motility. A mutant lacking SLP-76-binding sites (M12) blocked LFA-1 costimulation of IL-2 production, polarization, and motility. LFA-1-ADAP polarization was also dependent on src kinases, Rho GTPases, phospholipase C, and phosphoinositol 3-kinase. Our findings provide evidence of an obligatory role for the SLP-76-ADAP module in LFA-1-mediated costimulation in T cells.
尽管衔接蛋白ADAP（FYB）及其与SLP-76的结合参与了T细胞中T细胞受体（TcR）诱导的LFA-1激活的“由内向外”信号传导，但关于其在LFA-1介导的“由外向内”信号传导中的作用却知之甚少。在本研究中，我们证明ADAP和SLP-76-ADAP结合与LFA-1共刺激IL-2产生、F-肌动蛋白聚集、细胞极化和T细胞运动性相关。LFA-1增强抗CD3诱导的IL-2产生完全依赖于SLP-76-ADAP结合。此外，发现抗CD3需要通过抗体或ICAM1进行CD11a连接才能引起T细胞极化。ADAP增强了抗CD3/CD11a诱导的这种极化，但单独抗CD3则不能。单独的LFA-1连接时ADAP的表达足以直接使T细胞极化并增加T细胞运动性，而ADAP基因敲除的原代T细胞中ADAP的缺失则降低了运动性。缺乏SLP-76结合位点的突变体（M12）阻断了LFA-1对IL-2产生、极化和运动性的共刺激。LFA-1-ADAP极化也依赖于src激酶、Rho GTP酶、磷脂酶C和磷酸肌醇3激酶。我们的研究结果提供了证据，证明SLP-76-ADAP模块在T细胞中LFA-1介导的共刺激中起关键作用。
