Department of Immunology, College of Medicine, Mayo Clinic, Rochester, MN 55905, United States.
Mol Immunol. 2011 May;48(9-10):1149-59. doi: 10.1016/j.molimm.2011.02.008. Epub 2011 Mar 25.
2B4 is a member of the SLAM receptor family capable of activating NK cell cytotoxicity in the context of EBV infection. SAP (SLAM Associated Protein) deficiency causes defective signaling downstream of SLAM family receptors and high susceptibility to EBV. 2B4 costimulates natural cytotoxicity receptor (NCR) and TCR initiated signals to induce cellular cytotoxicity and cytokine release. The 2B4-SAP signal transduction pathway is not predicted to overlap with the TCR-ITAM pathway, although SAP is required for some TCR-induced signals. We therefore examined the functional relationship between SLAM family receptor 2B4 and ITAM-containing adaptor complexes. Removal of FcɛRIγ or CD3ζ-containing complexes, using genetically manipulated cell lines or siRNA specific suppression, significantly reduces 2B4-initiated functions in NK and T cells, respectively. Consistent with this relationship, Syk and ZAP-70 are capable of transducing 2B4 signals for calcium mobilization and cytolysis. Furthermore, ITAM-containing molecules constitutively associate with SAP. These results suggest a potential physical association between 2B4 and the ITAM receptor complexes that is required for 2B4-initiated signaling and cell-mediated killing.
2B4 是 SLAM 受体家族的一员，能够在 EBV 感染的情况下激活 NK 细胞的细胞毒性。SAP（SLAM 相关蛋白）缺乏会导致 SLAM 家族受体下游的信号传导缺陷，并使 EBV 易感性增加。2B4 共刺激自然细胞毒性受体（NCR）和 TCR 启动的信号，以诱导细胞毒性和细胞因子释放。虽然 SAP 是一些 TCR 诱导信号所必需的，但 2B4-SAP 信号转导途径预计不会与 TCR-ITAM 途径重叠。因此，我们研究了 SLAM 家族受体 2B4 和包含 ITAM 的衔接复合物之间的功能关系。使用基因改造的细胞系或 siRNA 特异性抑制去除 FcɛRIγ 或 CD3ζ 包含的复合物，分别显著降低 NK 和 T 细胞中 2B4 起始的功能。与这种关系一致，Syk 和 ZAP-70 能够转导 2B4 信号以进行钙动员和细胞溶解。此外，包含 ITAM 的分子与 SAP 组成性地关联。这些结果表明 2B4 和 ITAM 受体复合物之间存在潜在的物理关联，这对于 2B4 起始的信号转导和细胞介导的杀伤是必需的。
