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 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.

Systemic administration of monovalent follistatin-like 3-Fc-fusion protein increases muscle mass in mice

“…Skeletal muscle secretes several cytokines and proteins named myokines, and it also functions as a primary site for glucose uptake and metabolism ( Cruz-Jentoft and Sayer, 2019 ; Johnson et al., 2013 ; Lee and Jun, 2019 ). In addition, skeletal muscle is reported to induce a microenvironment with less inflammation, sheltering a population of T cells from systemic inflammation and preventing their exhaustion ( Wu et al., 2020 ). Aging and various systemic diseases are associated with a decrease in the mass and function of skeletal muscle, which not only reduces the quality of life of patients but also leads to higher morbidity and mortality ( Cruz-Jentoft and Sayer, 2019 ; Johnson et al., 2013 ).…”

Multi–Omics Analysis of Key microRNA–mRNA Metabolic Regulatory Networks in Skeletal Muscle of Obese Rabbits

“…The TLR4 signaling pathway and other pattern recognition receptors (PRRS) in muscle cells can respond to inflammatory signals and influence metabolic changes [ 39 ]. The T cells and macrophages are involved in the production of inflammatory cytokines and insulin resistance in skeletal muscle [ 40 , 41 ]. Similarly, we found that Th17 cell differentiation, antigen processing and presentation, and chemokine signaling pathways were upregulated in the skeletal muscle of obese rabbits in the HFD-G group.…”

SARS-CoV-2 and mitochondrial health: implications of lifestyle and ageing

“…Muscle has now been shown to have other functions, like harbouring and supplying anti-viral stem T-cells, hence, antagonising T-cell exhaustion and protecting proliferative potential during inflammation [ 127 ]. In contrast white adipose tissue plays a key role in adaptive immunity, and in excess, contributes to the altered immune function and chronic inflammation often associated with obesity [ 128 ].…”