Hamel M E, Noteboom E, Kruisbeek A M
Division of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Immunology. 1998 Mar;93(3):366-75. doi: 10.1046/j.1365-2567.1998.00443.x.
We recently reported that previously activated T cells, irrespective of the nature of the first stimulus they encountered, are unable to respond to Staphylococcal enterotoxin B (SEB), nor to soluble anti-CD3 monoclonal antibody (mAb) presented by splenic antigen-presenting cells (APC). Such previously activated T cells are, however, fully capable of responding to plate-bound anti-CD3 plus splenic APC. These data suggest differential integration of the T-cell receptor (TCR) and co-stimulatory signalling pathways in naive versus antigen-experienced T cells. Consistent with this hypothesis, anti-CD28 mAb restores the proliferative capacity of resting ex vivo CD45RBlo CD4+ T cells (representing previously activated T cells) to both soluble anti-CD3 mAb and SEB. Interestingly, mAb-mediated engagement of cytotoxic T-lymphocyte antigen-4 (CTLA-4) completely negates the rescue effects mediated by anti-CD28 mAb in CD45RBlo cells. Nevertheless, the non-responsiveness of CD45RBlo CD4+ T cells cannot be reversed by anti-CTLA-4 Fab fragments, indicating that it is not related to negative regulatory effects of CTLA-4 engagement itself. Interestingly, the addition of interleukin-2 (IL-2) restores the proliferative capacity of CD45RBlo CD4+ T cells to SEB and soluble anti-CD3 mAb. Moreover, when rescued by IL-2, the cells are less susceptible to the negative regulatory effects of CTLA-4 engagement. Together, these findings suggest that the non-responsiveness of CD45RBlo CD4+ T cells to certain stimuli may be related to inadequate TCR signalling, primarily affecting IL-2 production.
我们最近报道，先前被激活的T细胞，无论它们遇到的第一种刺激的性质如何，都无法对葡萄球菌肠毒素B（SEB）作出反应，也无法对脾抗原呈递细胞（APC）呈递的可溶性抗CD3单克隆抗体（mAb）作出反应。然而，这些先前被激活的T细胞完全有能力对板结合的抗CD3加脾APC作出反应。这些数据表明，在未成熟T细胞与抗原经历过的T细胞中，T细胞受体（TCR）和共刺激信号通路的整合存在差异。与该假设一致，抗CD28 mAb可恢复静息的体外CD45RBlo CD4+ T细胞（代表先前被激活的T细胞）对可溶性抗CD3 mAb和SEB的增殖能力。有趣的是，单克隆抗体介导的细胞毒性T淋巴细胞抗原4（CTLA-4）的结合完全抵消了抗CD28 mAb在CD45RBlo细胞中介导的拯救作用。然而，CD45RBlo CD4+ T细胞的无反应性不能被抗CTLA-4 Fab片段逆转，这表明它与CTLA-4结合本身的负调节作用无关。有趣的是，添加白细胞介素-2（IL-2）可恢复CD45RBlo CD4+ T细胞对SEB和可溶性抗CD3 mAb的增殖能力。此外，当被IL-2拯救时，这些细胞对CTLA-4结合的负调节作用更不敏感。总之，这些发现表明，CD45RBlo CD4+ T细胞对某些刺激的无反应性可能与TCR信号不足有关，主要影响IL-2的产生。
