J Clin Invest. 2021 Jun 1;131(11). doi: 10.1172/JCI149934.
Calcineurin inhibitors (CNIs) such as cyclosporin A and FK506 are widely administered immunosuppressive drugs. Calcineurin relieves inhibitory phosphorylation from nuclear factor of activated T cells (NFAT) transcription factors downstream of T cell receptor engagement, resulting in their nuclear translocation and the production of cytokines, including IL-2, IFN-γ, and TNF-α. It was previously believed that CNIs downregulate immunity by reducing NFAT activation. However, work from Otsuka et al. in this issue of the JCI revealed a second mechanism by which CNIs suppress T cell function. The authors previously reported that calcineurin removes an inhibitory phosphate from the tyrosine kinase Lck at Ser59 (Lck-S59) and that this dephosphorylation positively regulates T cell activation. In the present work, the authors showed that inhibition of Lck-S59 dephosphorylation was essential for the CNI-mediated suppression of acute graft-versus-host disease (aGVHD). These findings have important implications for future approaches to the management of aGVHD, organ transplant rejection, and autoimmune disease.
钙调磷酸酶抑制剂（CNIs），如环孢素 A 和 FK506，是广泛应用的免疫抑制剂。钙调磷酸酶可解除 T 细胞受体激活后核因子活化 T 细胞（NFAT）转录因子的抑制性磷酸化，导致其核易位及细胞因子（包括 IL-2、IFN-γ 和 TNF-α）的产生。先前认为 CNI 通过减少 NFAT 激活来下调免疫。然而，Otsuka 等人在本期 JCI 上的工作揭示了 CNI 抑制 T 细胞功能的第二种机制。作者先前报道钙调磷酸酶可从酪氨酸激酶 Lck 的丝氨酸 59 位（Lck-S59）上去除一个抑制性磷酸基团，这种去磷酸化正向调节 T 细胞激活。在本工作中，作者表明抑制 Lck-S59 去磷酸化对于 CNI 介导的急性移植物抗宿主病（aGVHD）的抑制至关重要。这些发现对未来处理 aGVHD、器官移植排斥和自身免疫性疾病的方法具有重要意义。
