Dohlsten M, Hedlund G, Lando P A, Trowsdale J, Altmann D, Patarroyo M, Fischer H, Kalland T
Pharmacia-LEO Therapeutics AB, Malmö, Sweden.
Eur J Immunol. 1991 Jan;21(1):131-5. doi: 10.1002/eji.1830210120.
Staphylococcal enterotoxin A (SEA) binds to major histocompatibility complex (MHC) class II molecules on target cells and directs human cytotoxic T lymphocytes (CTL) of irrelevant nominal specificity to mediate strong cytotoxicity against target cells. In this report we describe the importance of ICAM-1 (CD54) expression on the target cell in SEA-dependent cell-mediated cytotoxicity (SDCC), utilizing murine L cells co-transfected with HLA-DR and ICAM-1. Human CTL mediated a low but significant cytotoxicity against HLA-DR2- and HLA-DR7-transfected cells after preincubation with SEA, but no reactivity towards uncoated HLA-DR2 and HLA-DR7 cells or SEA-coated ICAM-1-transfected and untransfected L cells. In contrast, a strong cytotoxic response was mediated by CTL against L cells co-transfected with HLA-DR2/ICAM-1 and HLA-DR7/ICAM-1. Similar cytotoxic activity of the CTL was seen at a 30-fold lower effector-to-target cell ratio when comparing the HLA-DR2/ICAM-1-expressing cells with the HLA-DR2-expressing cells. SEA dose-response analysis demonstrated that the HLA-DR2/ICAM-1-expressing target cells enabled the CTL to respond to a 1000-fold lower concentration of SEA in comparison to the HLA-DR2-expressing cells. CD3+CD4+ and CD3+CD8+ cytotoxic T cell lines were equally dependent on the expression of ICAM-1 on the target cell. The strong CTL activity against HLA-DR2/ICAM-1-transfected cells could be blocked by anti-CD11a or anti-CD18 monoclonal antibodies (mAb), but not by anti-CD11b, anti-CD11c, anti-CD2 or unrelated control mAb. The great sensitivity of HLA-DR2/ICAM-1 expressing target cells to SDCC was strongly reduced by preincubation with various anti-ICAM-1 mAb but not by mAb against monomorphic HLA-DR or murine MHC class I determinants. The result in this study clearly demonstrates that efficient re-targeting of human CTL by SE is dependent on a proper interaction with the heterodimer CD11a/CD18 (Leu-CAMa, LFA-1) on the CTL and its target cell ligand ICAM-1.
葡萄球菌肠毒素A（SEA）与靶细胞上的主要组织相容性复合体（MHC）II类分子结合，并引导具有无关名义特异性的人细胞毒性T淋巴细胞（CTL）介导对靶细胞的强烈细胞毒性。在本报告中，我们利用共转染了HLA-DR和ICAM-1的小鼠L细胞，描述了ICAM-1（CD54）在靶细胞上的表达在SEA依赖性细胞介导的细胞毒性（SDCC）中的重要性。人CTL在与SEA预孵育后，对转染了HLA-DR2和HLA-DR7的细胞介导了低但显著的细胞毒性，但对未包被的HLA-DR2和HLA-DR7细胞或SEA包被的ICAM-1转染和未转染的L细胞无反应性。相比之下，CTL对共转染了HLA-DR2/ICAM-1和HLA-DR7/ICAM-1的L细胞介导了强烈的细胞毒性反应。当将表达HLA-DR2/ICAM-1的细胞与表达HLA-DR2的细胞进行比较时，在效应细胞与靶细胞比例低30倍的情况下，CTL仍具有相似的细胞毒性活性。SEA剂量反应分析表明与表达HLA-DR2的细胞相比，表达HLA-DR2/ICAM-1的靶细胞能使CTL对低1000倍浓度的SEA产生反应。CD3 + CD4 +和CD3 + CD8 +细胞毒性T细胞系同样依赖于靶细胞上ICAM-1的表达。针对表达HLA-DR2/ICAM-1的细胞的强烈CTL活性可被抗CD11a或抗CD18单克隆抗体（mAb）阻断，但不能被抗CD11b、抗CD11c、抗CD2或无关对照mAb阻断。用各种抗ICAM-1 mAb预孵育可显著降低表达HLA-DR2/ICAM-1的靶细胞对SDCC的高度敏感性，但针对单态性HLA-DR或小鼠MHC I类决定簇的mAb则无此作用。本研究结果清楚地表明，SEA对人CTL的有效重新靶向依赖于其与CTL上的异二聚体CD11a/CD18（白细胞黏附分子α，LFA-1）及其靶细胞配体ICAM-1的适当相互作用。
