Although skeletal muscles are not traditionally considered to be constituents of the immune system, the loss of skeletal muscle mass in chronic infection is frequently associated with impaired T cell function, or “T cell exhaustion.” Whether and how muscles regulate T cell exhaustion is unknown. We found that skeletal muscles antagonized T cell exhaustion in mice chronically infected with lymphocytic choriomeningitis virus (LCMV) clone 13. Spleen-derived exhausted CD8+ skeletal muscle-infiltrating lymphocytes (SMILEs) formed clusters in muscles where their antiviral function and proliferative potential were restored. These revived CD8+ SMILEs egressed from muscles and migrated back to lymphoid organs to sustain long-term antiviral immunity. We aim to understand how skeletal muscles regulate antiviral CD8+ T cell function, metabolism, and migration.
(1) Using metabolomics and RNA-sequencing approaches, we identified 46 metabolites that were enriched in muscle interstitial fluid and two myokine-encoding genes that were upregulated in muscle tissue, respectively. We plan to test whether and how these metabolites and myokines restore the antiviral functions of exhausted CD8+ T cells.
(2) We found that the CD8+ T cell migration between the spleen and skeletal muscles was guided by a protein gradient of regulator of G protein signaling 16 (Rgs16). We plan to identify the Rgs16-interacting partners and the molecular mechanisms underlying Rgs16 protein gradient-driven CD8+ T cell migration.
(3) We observed that increasing muscle mass using a genetic approach resulted in both increased numbers of CD8+ SMILEs and decreased viral titers in LCMV clone 13 infected mice. We plan to explore the therapeutic potential of increasing muscle mass for enhancing protective T cell responses in chronic infections.
Collectively, we will study the role of muscles in “recharging” exhausted T cells and will evaluate the therapeutic potential of increasing muscle mass in chronic infections
Fields of science
- HORIZON.1.1 - European Research Council (ERC) Main Programme