Van Gool S W, Vandenberghe P, de Boer M, Ceuppens J L
Department of Pathophysiology, Catholic University of Leuven, Belgium.
Immunol Rev. 1996 Oct;153:47-83. doi: 10.1111/j.1600-065x.1996.tb00920.x.
In this review, a sequential multiple-step model for T-cell activation is proposed. In a series of in vitro studies, highly purified freshly isolated human peripheral blood T lymphocytes were stimulated through the CD28 receptor, with mAb or with natural ligands B7-1 or B7-2, along with TCR stimulation, in the absence of other costimulatory interactions. Ligation of the CD28 receptor, along with stimulation of the TCR, was found to up-regulate pleiotropic in vitro activities, including the secretion of both Th1 and Th2-type cytokines, B-cell help, and the development of cytotoxic activity. This costimulatory action involves CD4+ and CD8+ as well as naive and memory T-cell subsets. The expression of B7-1 and B7-2 on professional APC in situ in both normal and pathological tissues, and its up-regulation on monocytes by GM-CSF and IFN-gamma is consistent with this role. Additional studies have addressed the contribution of interactions between CD28 and B7-1 and B7-2 in T-cell activation initiated by normal un-engineered APC, such as stimulation with recall antigens and primary MLR. Blockade of the interaction between CD28 and B7-1/B7-2 under these conditions failed to completely inhibit T-cell responses or to induce anergy. Complete inhibition and anergy were, however, induced with a combination of CsA, targeting downstream TCR-triggered signalling, as well as anti-B7-1- and anti-B7-2-directed reagents. Interestingly, and in contrast to anti-LFA-1 mAb, the addition of anti-B7-1 or anti-B7-2 reagents could be delayed until at least 48 h after the initiation of T-cell stimulation, indicating a requirement for a late interaction between CD28 and its counter-receptors. Interactions between CD40L on activated T cells and CD40 on APC may serve to sustain, enhance or prolong the presentation of B7-1 or B7-2 on the APC, and thus to prevent anergy induction, or ineffective or abortive T-cell stimulation. Based on these data a sequential multiple-step T-cell activation model is proposed, and novel strategies for immuno-intervention can be designed.
在本综述中，提出了一种T细胞激活的连续多步骤模型。在一系列体外研究中，高度纯化的新鲜分离的人外周血T淋巴细胞在不存在其他共刺激相互作用的情况下，通过CD28受体、单克隆抗体或天然配体B7-1或B7-2进行刺激，并同时进行TCR刺激。发现CD28受体的结合以及TCR的刺激可上调多效性体外活性，包括Th1和Th2型细胞因子的分泌、B细胞辅助以及细胞毒性活性的发展。这种共刺激作用涉及CD4+和CD8+以及幼稚和记忆T细胞亚群。正常和病理组织中原位专业APC上B7-1和B7-2的表达，以及GM-CSF和IFN-γ对单核细胞上其表达上调，均与此作用一致。其他研究探讨了CD28与B7-1和B7-2之间的相互作用在由正常未工程化APC引发的T细胞激活中的作用，例如用回忆抗原和原发性混合淋巴细胞反应进行刺激。在这些条件下阻断CD28与B7-1/B7-2之间的相互作用未能完全抑制T细胞反应或诱导无反应性。然而，通过靶向TCR触发的下游信号传导的环孢素A以及抗B7-1和抗B7-2导向的试剂的组合诱导了完全抑制和无反应性。有趣的是，与抗LFA-1单克隆抗体相反，抗B7-1或抗B7-2试剂的添加可以延迟到T细胞刺激开始后至少48小时，这表明CD28与其反受体之间需要晚期相互作用。活化T细胞上的CD40L与APC上的CD40之间的相互作用可能有助于维持、增强或延长APC上B7-1或B7-2的呈递，从而防止无反应性诱导或无效或流产的T细胞刺激。基于这些数据，提出了一种连续多步骤T细胞激活模型，并可设计新的免疫干预策略。
