Project description
Mechanism of recharging exhausted T cells by skeletal muscles
Scientists associate the loss of skeletal muscle mass in chronic infection with impaired T cell function or T cell exhaustion, but the mechanisms of T cell restoration by muscle mass are not understood. Recent studies showed that skeletal muscles antagonised T cell exhaustion in mice chronically infected with lymphocytic choriomeningitis virus. Also, the spleen-derived exhausted CD8+ skeletal muscle-infiltrating lymphocytes formed clusters in muscles, restoring their potential and migrating back to lymphoid organs, providing long-term antiviral immunity. The EU-funded MuscleAntiVirus project aims to understand how skeletal muscles regulate antiviral CD8+ T cell function, metabolism, and migration. The objective is to uncover mechanisms of muscle-linked T cell ‘recharging’ and the therapeutic potential of increased muscle mass in chronic infections.
Objective
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 (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences microbiology virology
- natural sciences biological sciences biochemistry biomolecules proteins
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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HORIZON.1.1 - European Research Council (ERC)
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(opens in new window) ERC-2021-COG
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69120 Heidelberg
Germany
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