Calvo C R, Amsen D, Kruisbeek A M
Division of Immunology, The Netherlands Cancer Institute, Amsterdam.
J Exp Med. 1997 Nov 17;186(10):1645-53. doi: 10.1084/jem.186.10.1645.
Cytotoxic T lymphocyte antigen 4 (CTLA-4) is an important regulator of T cell homeostasis. Ligation of this receptor leads to prominent downregulation of T cell proliferation, mainly as a consequence of interference with IL-2 production. We here report that CTLA-4 engagement strikingly selectively shuts off activation of downstream T cell receptor (TCR)/CD28 signaling events, i.e., activation of the microtubule-associated protein kinase (MAPKs) ERK and JNK. In sharp contrast, proximal TCR signaling events such as ZAP70 and TCR-zeta chain phosphorylation are not affected by CTLA-4 engagement on activated T cells. Since activation of the ERK and JNK kinases is required for stimulation of interleukin (IL)-2 transcription, these data provide a molecular explanation for the block in IL-2 production imposed by CTLA-4.
细胞毒性T淋巴细胞抗原4（CTLA-4）是T细胞稳态的重要调节因子。该受体的结合导致T细胞增殖显著下调，主要是由于干扰白细胞介素-2（IL-2）的产生。我们在此报告，CTLA-4的结合显著选择性地关闭下游T细胞受体（TCR）/CD28信号事件的激活，即微管相关蛋白激酶（MAPK）ERK和JNK的激活。与之形成鲜明对比的是，近端TCR信号事件，如ZAP70和TCR-zeta链磷酸化，不受激活的T细胞上CTLA-4结合的影响。由于ERK和JNK激酶的激活是刺激白细胞介素（IL）-2转录所必需的，这些数据为CTLA-4对IL-2产生的阻断提供了分子解释。
