Damle N K, Klussman K, Leytze G, Aruffo A, Linsley P S, Ledbetter J A
Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, WA 98121.
J Immunol. 1993 Sep 1;151(5):2368-79.
Integrin ligands intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) can efficiently costimulate proliferation of resting T cells but not that of Ag-specific T cells. In contrast, CD28 ligand B7 and CD2 ligand leukocyte function-associated Ag (LFA-3) can support IL-2 synthesis and proliferation of Ag-specific T cells more efficiently than that of resting T cells. The molecular basis for this differential costimulation of T cells is poorly understood. In this study, using mAb and soluble IgC gamma 1 chimeras of these adhesion molecules, we demonstrate that coligation of the TCR and CD11a/CD18 (LFA-1/beta 2 integrin) or CD29/CD49d (very late activation Ag-4/beta 1 integrin) using anti-TCR mAb and either ICAM-1 or VCAM-1 induces activation-dependent death of DRw6-specific CD4+ T cells. Similar coligation of the TCR with CD2 or CD28 using either mAb or ligands LFA-3 or B7 not only lacked the ability to induce death but also failed to reverse or inhibit integrin-facilitated death of DRw6-specific T cells. Each of these ligands augmented anti-TCR mAb-induced transcription of IL-2 and IL-4 genes. Exogenous addition of IL-2 and IL-4 did not reverse the integrin-supported T cell death. The death-promoting costimulatory effects of ICAM-1 and VCAM-1 were observed with Ag-specific chronically stimulated T cells but not with either resting T cells or those activated in short-term cultures. Treatment of T cells with cyclosporin A or a protein tyrosine kinase inhibitor herbimycin A inhibited ICAM-1 or VCAM-1-promoted activation-induced T cell death. The Ag-specific T cells that survived death-promoting effects of ICAM-1 or VCAM-1 proliferated efficiently upon restimulation with these ligands. Exposure of DRw6-specific T cells to DRw6+ B7+ ICAM-1+ LFA-3+ VCAM-1+ APC but not DR3+ B7+ ICAM-1+ LFA-3+ VCAM-1+ APC induced death of these T cells. This effect was blocked by pretreatment of T cells with mAb directed at CD18 or CD29 but not with those against CD2 or CD28. Taken together, these results suggest that TCR-directed engagement of integrins by their ligands ICAM-1 or VCAM-1 induces activation-dependent death of some perhaps more differentiated Ag-specific T cells and this may be an important homeostatic mechanism by which functional expression of Ag-specific T cells is regulated during an ongoing immune response.
整合素配体细胞间黏附分子-1（ICAM-1）和血管细胞黏附分子-1（VCAM-1）能够有效地共刺激静息T细胞增殖，但不能刺激抗原特异性T细胞增殖。相比之下，CD28配体B7和CD2配体白细胞功能相关抗原（LFA-3）比静息T细胞更能有效地支持抗原特异性T细胞的白细胞介素-2合成和增殖。T细胞这种差异性共刺激的分子基础尚不清楚。在本研究中，我们使用这些黏附分子的单克隆抗体和可溶性IgCγ1嵌合体，证明使用抗TCR单克隆抗体与ICAM-1或VCAM-1共同连接TCR和CD11a/CD18（LFA-1/β2整合素）或CD29/CD49d（极晚期活化抗原-4/β1整合素）会诱导DRw6特异性CD4+T细胞的活化依赖性死亡。使用单克隆抗体或配体LFA-3或B7将TCR与CD2或CD28进行类似的共同连接，不仅缺乏诱导死亡的能力，而且无法逆转或抑制整合素促进的DRw6特异性T细胞死亡。这些配体中的每一种都增强了抗TCR单克隆抗体诱导的白细胞介素-2和白细胞介素-4基因转录。外源性添加白细胞介素-2和白细胞介素-4并不能逆转整合素支持的T细胞死亡。在抗原特异性慢性刺激的T细胞中观察到ICAM-1和VCAM-1的促死亡共刺激作用，但在静息T细胞或短期培养中活化的T细胞中未观察到。用环孢素A或蛋白酪氨酸激酶抑制剂赫曲霉素A处理T细胞可抑制ICAM-1或VCAM-1促进的活化诱导的T细胞死亡。在经受ICAM-1或VCAM-1的促死亡作用后存活的抗原特异性T细胞在用这些配体再次刺激时能有效增殖。将DRw6特异性T细胞暴露于DRw6+B7+ICAM-1+LFA-3+VCAM-1+抗原呈递细胞（APC）而不是DR3+B7+ICAM-1+LFA-3+VCAM-1+APC会诱导这些T细胞死亡。用针对CD18或CD29的单克隆抗体预处理T细胞可阻断这种效应，但用针对CD2或CD28的单克隆抗体则不能。综上所述，这些结果表明，其配体ICAM-1或VCAM-1通过TCR介导的整合素结合会诱导一些可能更分化的抗原特异性T细胞的活化依赖性死亡，这可能是一种重要的稳态机制，通过该机制在正在进行的免疫反应过程中调节抗原特异性T细胞的功能表达。
