CD80, CD86 and CD40 Provide Accessory Signals in a Multiple‐Step T‐Cell Activation Model

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.