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Skeletal muscle antagonizes antiviral CD8+ T cell exhaustion.


ABSTRACT: 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 Il15 enhanced the CD8+ T cell exhaustion phenotype. Muscle-derived IL-15 was required to maintain a population of CD8+CD103+ 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 TGF? 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.

SUBMITTER: Wu J 

PROVIDER: S-EPMC7292629 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Skeletal muscle antagonizes antiviral CD8<sup>+</sup> T cell exhaustion.

Wu Jingxia J   Weisshaar Nina N   Hotz-Wagenblatt Agnes A   Madi Alaa A   Ma Sicong S   Mieg Alessa A   Hering Marvin M   Mohr Kerstin K   Schlimbach Tilo T   Borgers Helena H   Cui Guoliang G  

Science advances 20200612 24


CD8<sup>+</sup> 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 <i>Il15</i> enhanced the CD8<sup>+</sup> T cell exhaustion phenotype. Muscle-derived IL-15 was required to maintain a p  ...[more]

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