Skeletal Muscles Antagonize T Cell Exhaustion in Chronic Viral Infections

Informations projet

MuscleAntiVirus

N° de convention de subvention: 101045416

DOI

10.3030/101045416

Projet clôturé le 12 Février 2024

Date de signature de la CE 25 Mai 2022

Date de début 1 Juin 2022

Date de fin 31 Mai 2027

Financé au titre de

• European Research Council (ERC)

Coût total

€ 2 000 000,00

Contribution de l’UE

€ 2 000 000,00

Coordonné par

DEUTSCHES KREBSFORSCHUNGSZENTRUM HEIDELBERG
Germany

Periodic Reporting for period 1 - MuscleAntiVirus (Skeletal Muscles Antagonize T Cell Exhaustion in Chronic Viral Infections)

Période du rapport: 2022-06-01 au 2024-11-30

Résumé du contexte et des objectifs généraux du projet

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) We plan to test whether and how metabolites (such as amino acid derivatives and sphingolipids) 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.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

With the generous support of this ERC grant, I have published two last-author manuscripts (Weisshaar et al., Science Immunology (2022); Weisshaar et al., Nature Immunology (2023)). This ERC grant is also acknowledged in these two papers.

1 Nina Weisshaar, Sicong Ma, Yanan Ming, Alaa Madi, Alessa Mieg, Marvin Hering, Ferdinand Zettl, Kerstin Mohr, Nora Ten Bosch, Diana Stichling, Michael Buettner, Gernot Poschet, Glynis Klinke, Michael Schulz, Nina Kunze-Rohrbach, Carolin Kerber, Isabel Madeleine Klein, Jingxia Wu#, Xi Wang# & Guoliang Cui#. The malate shuttle detoxifies ammonia in exhausted T cells by producing 2-ketoglutarate. Nature Immunology 24, 1921-1932, doi:10.1038/s41590-023-01636-5 (2023). (#co-corresponding authors).

2 Nina Weisshaar, Jingxia Wu, Yanan Ming, Alaa Madi, Agnes Hotz-Wagenblatt, Sicong Ma, Alessa Mieg, Marvin Hering, Ferdinand Zettl, Kerstin Mohr, Tilo Schlimbach, Nora Ten Bosch, Franziska Hertel, Lisann Müller, Hannah Byren, Mona Wang, Helena Borgers, Mareike Munz, Lukas Schmitt, Franciscus van der Hoeven, Ulrich Kloz, Rafael Carretero, Nikolai Schleußner, Rene-Filip Jackstadt, Ilse Hofmann & Guoliang Cui. Rgs16 promotes antitumor CD8+ T cell exhaustion. Science Immunology 7, eabh1873, doi:doi:10.1126/sciimmunol.abh1873 (2022).

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

Cancer and chronic viral infections are often associated with the loss of muscle mass and functional impairment or “exhaustion” of anti-tumor and antiviral T cells. The funded research program helps to elucidate the immunological functions of skeletal muscles. These studies have an impact on understanding the role of exercises and muscle mass in antiviral immunity.

First, it is known from the COVID-19 pandemic that aged and obese individuals were more susceptible to infections and developed less efficient responses to vaccines compared to young and lean individuals. However, the molecular mechanisms are incompletely understood. In our study, we have identified the underlying biochemical basis and also proposed that supplementing a small molecule, 3-IPA, increased the antiviral immunity in the aged and obese individuals.

Second, we identified a previously uncharacterized protein, Rgs16, as an inhibitor of CD8+ T cell effector function. Rgs16 displays a similar biological function as the “star” molecule in the field of immunotherapy, PD-1, but also shows a difference. For example, Rgs16 deficiency does not cause immunodeficiency, suggesting the therapeutic window of inhibiting Rgs16 is potentially bigger than blocking PD-1. We further identified the molecular mechanisms through which Rgs16 regulates T cell function.

Collectively, these studies do not only promote basic scientific research but also reveal therapeutic targets to boost antiviral immunity.

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