Wu Y, Guo Y, Huang A, Zheng P, Liu Y
Department of Pathology, New York University Medical Center, New York 10016, USA.
J Exp Med. 1997 Apr 7;185(7):1327-35. doi: 10.1084/jem.185.7.1327.
T cell costimulation, particularly by the B7 family members B7-1 and B7-2, plays a critical role in regulating T cell-mediated immunity. Two molecules on T cells, CD28 and CTLA-4, are known to bind to B7. It has been suggested that CD28-B7 interaction promotes T cell response, whereas B7-CTLA-4 interaction downregulates T cell clonal expansion. However, the proposed responses of individual receptors to B7 have not been verified directly. Here, we report that B7-1 promotes clonal expansion of CD28-deficient T cells, and that the CD28-independent costimulatory activity is mediated by CTLA-4, as it is completely blocked by intact and Fab of anti-CTLA-4 mAb. In addition, a mutant B7-1 molecule, B7W88 >A, which has lost binding to CD28 but retained significant CTLA-4 binding activity, promotes T cell clonal expansion. Furthermore, while presence of CD28 enhances T cell response to B7-1, such response is also completely blocked by anti-CTLA-4 mAb. Taken together, our results demonstrate that B7-CTLA-4 interaction promotes T cell clonal expansion, and that optimal T cell response to B7 is achieved when both CD28 and CTLA-4 interact with B7. These results establish an important function of CTLA-4 in promoting T cell activation, and suggest an alternative interpretation of the function of CTLA-4 in T cell activation.
T细胞共刺激，尤其是由B7家族成员B7-1和B7-2介导的共刺激，在调节T细胞介导的免疫中起着关键作用。已知T细胞上的两种分子CD28和CTLA-4可与B7结合。有人提出，CD28-B7相互作用促进T细胞反应，而B7-CTLA-4相互作用则下调T细胞克隆扩增。然而，单个受体对B7的上述反应尚未得到直接验证。在此，我们报告B7-1促进CD28缺陷型T细胞的克隆扩增，且不依赖CD28的共刺激活性由CTLA-4介导，因为它完全被抗CTLA-4单克隆抗体的完整抗体和Fab片段所阻断。此外，一种突变的B7-1分子B7W88>A，它失去了与CD28的结合，但保留了显著的CTLA-4结合活性，可促进T细胞克隆扩增。此外，虽然CD28的存在增强了T细胞对B7-1的反应，但这种反应也完全被抗CTLA-4单克隆抗体所阻断。综上所述，我们的结果表明B7-CTLA-4相互作用促进T细胞克隆扩增，并且当CD28和CTLA-4都与B7相互作用时，T细胞对B7能产生最佳反应。这些结果确立了CTLA-4在促进T细胞活化中的重要功能，并提示了对CTLA-4在T细胞活化中功能的另一种解释。
