Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, United States of America.
Department of Pathology and Genomic Medicine, Houston Methodist Hospital Research Institute, Houston, TX, United States of America.
PLoS One. 2018 Aug 8;13(8):e0200752. doi: 10.1371/journal.pone.0200752. eCollection 2018.
Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) where pathology is thought to be regulated by autoreactive T cells of the Th1 and Th17 phenotype. In this study we sought to understand the functions of Presenilin 1 (PSEN1) in regulating T cell effector responses in the experimental autoimmune encephalomyelitis (EAE) murine model of MS. PSEN1 is the catalytic subunit of γ-secretase a multimolecular protease that mediates intramembranous proteolysis. γ-secretase is known to regulate several pathways of immune importance. Here we examine the effects of disrupting PSEN1 functions on EAE and T effector differentiation using small molecule inhibitors of γ-secretase (GSI) and T cell-specific conditional knockout mice (PSEN1 cKO). Surprisingly, blocking PSEN1 function by GSI treatment or PSEN1 cKO had little effect on the development or course of MOG35-55-induced EAE. In vivo GSI administration reduced the number of myelin antigen-specific T cells and suppressed Th1 and Th17 differentiation following immunization. In vitro, GSI treatment inhibited Th1 differentiation in neutral but not IL-12 polarizing conditions. Th17 differentiation was also suppressed by the presence of GSI in all conditions and GSI-treated Th17 T cells failed to induce EAE following adoptive transfer. PSEN cKO T cells showed reduced Th1 and Th17 differentiation. We conclude that γ-secretase and PSEN1-dependent signals are involved in T effector responses in vivo and potently regulate T effector differentiation in vitro, however, they are dispensable for EAE.
多发性硬化症（MS）是一种中枢神经系统（CNS）的炎症性脱髓鞘疾病，其病理学被认为是由 Th1 和 Th17 表型的自身反应性 T 细胞调节的。在这项研究中，我们试图了解早老素 1（PSEN1）在调节实验性自身免疫性脑脊髓炎（EAE）多发性硬化症小鼠模型中 T 细胞效应器反应中的作用。PSEN1 是 γ-分泌酶的催化亚基，γ-分泌酶是一种介导跨膜蛋白水解的多分子蛋白酶。γ-分泌酶已知调节几个免疫重要途径。在这里，我们使用 γ-分泌酶的小分子抑制剂（GSI）和 T 细胞特异性条件性敲除小鼠（PSEN1 cKO）来检查破坏 PSEN1 功能对 EAE 和 T 效应分化的影响。令人惊讶的是，用 GSI 处理或 PSEN1 cKO 阻断 PSEN1 功能对 MOG35-55 诱导的 EAE 的发展或病程几乎没有影响。体内 GSI 给药减少了髓鞘抗原特异性 T 细胞的数量，并抑制了免疫后的 Th1 和 Th17 分化。在体外，GSI 处理抑制了中性但不抑制 IL-12 极化条件下的 Th1 分化。在所有条件下，GSI 的存在也抑制了 Th17 分化，并且用 GSI 处理的 Th17 T 细胞在过继转移后不能诱导 EAE。PSEN cKO T 细胞显示出 Th1 和 Th17 分化减少。我们得出结论，γ-分泌酶和 PSEN1 依赖性信号参与体内 T 效应器反应，并在体外强烈调节 T 效应器分化，然而，它们对于 EAE 是可有可无的。
