Descrizione del progetto
I meccanismi adottati dai muscoli scheletrici per ricaricare le cellule T esaurite
Gli scienziati associano la perdita di massa muscolare scheletrica che si verifica nelle infezioni croniche ad alterazioni nella funzione delle cellule T, oppure al loro esaurimento. Tuttavia, i meccanismi alla base del ripristino di queste cellule da parte della massa muscolare non sono ben compresi. Secondo quanto dimostrato da studi recenti, i muscoli scheletrici hanno contrastato l’esaurimento delle cellule T in topi cronicamente infetti da virus della coriomeningite linfocitaria. Inoltre, i linfociti CD8+ esauriti originati nella milza e infiltranti il muscolo scheletrico hanno formato degli aggregati nei muscoli, ripristinandone il potenziale e migrando nuovamente verso gli organi linfoidi, con il risultato di fornire un’immunità antivirale a lungo termine. Il progetto MuscleAntiVirus, finanziato dall’UE, intende comprendere le modalità attraverso cui i muscoli scheletrici regolano la funzione, il metabolismo e la migrazione delle cellule T antivirali CD8+. L’obiettivo è quello di svelare i meccanismi alla base della «ricarica» delle cellule T legate ai muscoli e il potenziale terapeutico associato all’aumento della massa muscolare nelle infezioni croniche.
Obiettivo
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
Campo scientifico
Parole chiave
Programma(i)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Argomento(i)
Meccanismo di finanziamento
HORIZON-ERC - HORIZON ERC GrantsIstituzione ospitante
69120 Heidelberg
Germania