Wu Jingxia, Weisshaar Nina, Hotz-Wagenblatt Agnes, Madi Alaa, Ma Sicong, Mieg Alessa, Hering Marvin, Mohr Kerstin, Schlimbach Tilo, Borgers Helena, Cui Guoliang
T Cell Metabolism Group (D140), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany.
Sci Adv. 2020 Jun 12;6(24):eaba3458. doi: 10.1126/sciadv.aba3458. eCollection 2020 Jun.
CD8 T cells become functionally impaired or "exhausted" in chronic infections, accompanied by unwanted body weight reduction and muscle mass loss. Whether muscle regulates T cell exhaustion remains incompletely understood. We report that mouse skeletal muscle increased interleukin (IL)-15 production during LCMV clone 13 chronic infection. Muscle-specific ablation of enhanced the CD8 T cell exhaustion phenotype. Muscle-derived IL-15 was required to maintain a population of CD8CD103 muscle-infiltrating lymphocytes (MILs). MILs resided in a less inflamed microenvironment, expressed more T cell factor 1 (Tcf1), and had higher proliferative potential than splenic T cells. MILs differentiated into functional effector T cells after reentering lymphoid tissues. Increasing muscle mass via muscle-specific inhibition of TGFβ signaling enhanced IL-15 production and antiviral CD8 T cell responses. We conclude that skeletal muscle antagonizes T cell exhaustion by protecting T cell proliferative potential from inflammation and replenishing the effector T cell progeny pool in lymphoid organs.
在慢性感染中，CD8 T细胞功能受损或“耗竭”，同时伴有体重意外减轻和肌肉量减少。肌肉是否调节T细胞耗竭仍未完全明确。我们报告，在淋巴细胞脉络丛脑膜炎病毒（LCMV）克隆13慢性感染期间，小鼠骨骼肌中白细胞介素（IL）-15的产生增加。肌肉特异性敲除 增强了CD8 T细胞耗竭表型。维持一群CD8CD103肌肉浸润淋巴细胞（MIL）需要肌肉来源的IL-15。MIL存在于炎症较轻的微环境中，表达更多的T细胞因子1（Tcf1），并且比脾T细胞具有更高的增殖潜力。MIL重新进入淋巴组织后分化为功能性效应T细胞。通过肌肉特异性抑制转化生长因子β（TGFβ）信号增加肌肉量可增强IL-15的产生和抗病毒CD8 T细胞反应。我们得出结论，骨骼肌通过保护T细胞增殖潜力免受炎症影响并补充淋巴器官中的效应T细胞后代池来对抗T细胞耗竭。
