Damle N K, Klussman K, Leytze G, Ochs H D, Aruffo A, Linsley P S, Ledbetter J A
Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, Washington 98121.
Cell Immunol. 1993 Apr 15;148(1):144-56. doi: 10.1006/cimm.1993.1097.
Optimal stimulation of CD4+ T cells in an immune response requires not only signals transduced via the CD3/TCR complex but also costimulatory signals delivered as a consequence of interactions between T-cell surface-associated costimulatory R and their counter-R on APC. CD28 plays a crucial role as a dominant costimulatory R during the induction of CD4+ T-cell proliferation by interacting with counter-R B7 on APC to sustain IL-2 production. The absence of CD28-mediated costimulation has been postulated to result in T-cell anergy or unresponsiveness. The costimulatory effects of CD28 can be generated with its natural counter-R B7 or mAb directed at CD28. Using soluble C gamma 1 chimeras of B7, ICAM-1, and VCAM-1, we have recently shown that B7 costimulates TCR-dependent proliferation of Ag-primed CD4+ T cells more efficiently than that of resting nonactivated CD4+ T cells. In contrast, proliferation of resting CD4+ T cells can be efficiently costimulated by either ICAM-1 or VCAM-1 via interactions with their R CD11a/CD18 (LFA-1/beta 2 integrin) and CD29/CD49d (VLA-4/beta 1 integrin), respectively. TCR-directed preactivation of resting CD4+ T cells with ICAM-1 can induce increased responsiveness to B7 costimulation. In this study, we show that prior TCR-directed activation of resting CD4+ T cells with VCAM-1 induced increased responsiveness to B7 costimulation. VCAM-1 also synergized with B7 to bring about supraoptimal proliferation of CD4+ T cells. In addition, costimulation of resting T cells with VCAM-1 significantly increased not only surface expression of CD28 but also CD28-mediated mobilization of intracellular free [Ca2+]i. Similar activation of T cells with fibronectin also resulted in increased B7 responsiveness, suggesting the involvement of VLA-4 molecule. VCAM-1 costimulation induced hyperresponsiveness to B7 costimulation in both CD18+ (normal) and CD18- (leukocyte adhesion deficient) T cells. Thus, VCAM-1 may play an important costimulatory role during the activation of resting T cells and, by augmenting responsiveness to B7, facilitate optimal development of immunological memory in addition to various regulatory and effector functions.
在免疫应答中，对CD4+ T细胞的最佳刺激不仅需要通过CD3/TCR复合体转导的信号，还需要由于T细胞表面相关共刺激分子R与其在抗原呈递细胞（APC）上的配体R相互作用而传递的共刺激信号。CD28通过与APC上的配体B7相互作用，在诱导CD4+ T细胞增殖过程中作为主要共刺激分子发挥关键作用，以维持白细胞介素-2的产生。据推测，缺乏CD28介导的共刺激会导致T细胞无反应性或无应答。CD28的共刺激作用可以通过其天然配体B7或针对CD28的单克隆抗体产生。使用B7、细胞间黏附分子-1（ICAM-1）和血管细胞黏附分子-1（VCAM-1）的可溶性Cγ1嵌合体，我们最近表明，B7对已被抗原致敏的CD4+ T细胞的TCR依赖性增殖的共刺激作用比静息未激活的CD4+ T细胞更有效。相比之下，静息CD4+ T细胞的增殖可以分别通过ICAM-1或VCAM-1与它们的配体CD11a/CD18（淋巴细胞功能相关抗原-1/β2整合素）和CD29/CD49d（迟现抗原-4/β1整合素）相互作用而得到有效共刺激。用ICAM-1对静息CD4+ T细胞进行TCR导向的预激活可以诱导对B7共刺激的反应性增加。在本研究中，我们表明用VCAM-1对静息CD4+ T细胞进行预先的TCR导向激活可诱导对B7共刺激的反应性增加。VCAM-1还与B7协同作用，使CD4+ T细胞实现超最佳增殖。此外，用VCAM-1对静息T细胞进行共刺激不仅显著增加了CD28的表面表达，还增加了CD28介导的细胞内游离钙离子浓度（[Ca2+]i）的动员。用纤连蛋白对T细胞进行类似激活也导致对B7的反应性增加，提示迟现抗原-4分子参与其中。VCAM-1共刺激在CD18+（正常）和CD18-（白细胞黏附缺陷）T细胞中均诱导了对B7共刺激的高反应性。因此，VCAM-1可能在静息T细胞激活过程中发挥重要的共刺激作用，并且通过增强对B7的反应性，除了各种调节和效应功能外，还促进免疫记忆的最佳发育。
