Chikuma Shunsuke, Bluestone Jeffrey A
Diabetes Center, University of California at San Francisco, San Francisco, CA 94143-0540.
Immunol Res. 2003;28(3):241-53. doi: 10.1385/IR:28:3:241.
Potentially autoreactive T cells that escape negative selection in the thymus must be strictly controlled in the periphery to avoid autoimmune disease. The most robust regulatory process controlling autoreactivity is mediated by the CTLA-4-B7 pathway. The critical homeostasis mediated by CTLA-4 was proven using monoclonal antibodies and genetically disrupted CTLA-4 knockout mice that develop polyclonal lymphocyte activation and proliferation leading to massively enlarged lymph nodes and spleen and fatal multiorgan lymphocytic infiltrates. CTLA-4 ligation following T-cell activation downregulates cytokine production and cell-cycle progression, however, the proximal biochemical basis for robust T-cell regulation remains unclear. In this review, we summarize studies supporting a dynamic role for CTLA-4 at the immunological synapse leading to direct attenuation of early cell signals. A model is proposed based on these observations, which proposes that CTLA-4 may, in fact, function under some circumstances in a ligand-independent manner.
那些在胸腺中逃脱阴性选择的潜在自身反应性T细胞，必须在外周受到严格控制，以避免自身免疫性疾病。控制自身反应性的最有力调节过程是由CTLA-4-B7途径介导的。利用单克隆抗体和基因敲除CTLA-4的小鼠证明了CTLA-4介导的关键稳态，这些小鼠会发生多克隆淋巴细胞激活和增殖，导致淋巴结和脾脏大量肿大以及致命的多器官淋巴细胞浸润。T细胞激活后CTLA-4的结合会下调细胞因子的产生和细胞周期进程，然而，强大的T细胞调节的近端生化基础仍不清楚。在这篇综述中，我们总结了支持CTLA-4在免疫突触中发挥动态作用从而直接减弱早期细胞信号的研究。基于这些观察结果提出了一个模型，该模型认为CTLA-4实际上可能在某些情况下以不依赖配体的方式发挥作用。
