Trefzer Anne, Kadam Pallavi, Wang Shu-Hung, Pennavaria Stefanie, Lober Benedikt, Akçabozan Batuhan, Kranich Jan, Brocker Thomas, Nakano Naoko, Irmler Martin, Beckers Johannes, Straub Tobias, Obst Reinhard
Institute for Immunology, Biomedical Center, Medical Faculty, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany.
Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba 278-0022, Japan.
Cell Rep. 2021 Feb 9;34(6):108748. doi: 10.1016/j.celrep.2021.108748.
Exhausted immune responses to chronic diseases represent a major challenge to global health. We study CD4 T cells in a mouse model with regulatable antigen presentation. When the cells are driven through the effector phase and are then exposed to different levels of persistent antigen, they lose their T helper 1 (Th1) functions, upregulate exhaustion markers, resemble naturally anergic cells, and modulate their MAPK, mTORC1, and Ca/calcineurin signaling pathways with increasing dose and time. They also become unable to help B cells and, at the highest dose, undergo apoptosis. Transcriptomic analyses show the dynamic adjustment of gene expression and the accumulation of T cell receptor (TCR) signals over a period of weeks. Upon antigen removal, the cells recover their functionality while losing exhaustion and anergy markers. Our data suggest an adjustable response of CD4 T cells to different levels of persisting antigen and contribute to a better understanding of chronic disease.
对慢性疾病的免疫反应耗竭是全球健康面临的一项重大挑战。我们在一个具有可调节抗原呈递的小鼠模型中研究CD4 T细胞。当这些细胞经历效应阶段，然后暴露于不同水平的持续性抗原时，它们会丧失辅助性T细胞1（Th1）功能，上调耗竭标志物，类似于天然无反应性细胞，并随着剂量增加和时间推移调节其丝裂原活化蛋白激酶（MAPK）、哺乳动物雷帕霉素靶蛋白复合体1（mTORC1）以及钙/钙调神经磷酸酶信号通路。它们也变得无法辅助B细胞，并且在最高剂量时会发生凋亡。转录组分析显示在数周时间内基因表达的动态调整以及T细胞受体（TCR）信号的积累。去除抗原后，这些细胞恢复其功能，同时丧失耗竭和无反应性标志物。我们的数据表明CD4 T细胞对不同水平的持续性抗原具有可调节的反应，有助于更好地理解慢性疾病。
