Prostaglandin E2 controls the metabolic adaptation of T cells to the intestinal 
microenvironment

Villa, Matteo; Sanin, David E; Apostolova, Petya; Corrado, Mauro; Kabat, Agnieszka M; Cristinzio, Carmine; Regina, Annamaria; Carrizo, Gustavo E; Rana, Nisha; Stanczak, Michal A; Baixauli, Francesc; Grzes, Katarzyna M; Cupovic, Jovana; Solagna, Francesca; Hackl, Alexandra; Globig, Anna-Maria; Hässler, Fabian; Puleston, Daniel J; Kelly, Beth; Cabezas-Wallscheid, Nina; Hasselblatt, Peter; Bengsch, Bertram; Zeiser, Robert; Sagar,; Büscher, Jörg Martin; Pearce, Edward Jonathen; Pearce, Erika Laine

doi:10.1038/s41467-024-44689-2

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Prostaglandin E₂ controls the metabolic adaptation of T cells to the intestinal microenvironment

MPS-Authors

Villa, Matteo
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Sanin, David E
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Apostolova, Petya
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Corrado, Mauro
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Kabat, Agnieszka M
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Cristinzio, Carmine
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Regina, Annamaria
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Carrizo, Gustavo E
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Rana, Nisha
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Stanczak, Michal A
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Baixauli, Francesc
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Grzes, Katarzyna M
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Cupovic, Jovana
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Solagna, Francesca
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Hackl, Alexandra
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Hässler, Fabian
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Puleston, Daniel J
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Kelly, Beth
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

/persons/resource/persons204274

Cabezas-Wallscheid, Nina
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

/persons/resource/persons241896

Büscher, Jörg Martin
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

/persons/resource/persons201435

Pearce, Edward Jonathen
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

/persons/resource/persons201431

Pearce, Erika Laine
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Citation

Villa, M., Sanin, D. E., Apostolova, P., Corrado, M., Kabat, A. M., Cristinzio, C., et al. (2024). Prostaglandin E₂ controls the metabolic adaptation of T cells to the intestinal microenvironment. Nature Communications, 15: 451. doi:10.1038/s41467-024-44689-2.

Cite as: https://hdl.handle.net/21.11116/0000-000E-394A-0

Abstract

Immune cells must adapt to different environments during the course of an immune response. Here we study the adaptation of CD8⁺ T cells to the intestinal microenvironment and how this process shapes the establishment of the CD8⁺ T cell pool. CD8⁺ T cells progressively remodel their transcriptome and surface phenotype as they enter the gut wall, and downregulate expression of mitochondrial genes. Human and mouse intestinal CD8⁺ T cells have reduced mitochondrial mass, but maintain a viable energy balance to sustain their function. We find that the intestinal microenvironment is rich in prostaglandin E₂ (PGE₂), which drives mitochondrial depolarization in CD8⁺ T cells. Consequently, these cells engage autophagy to clear depolarized mitochondria, and enhance glutathione synthesis to scavenge reactive oxygen species (ROS) that result from mitochondrial depolarization. Impairing PGE₂ sensing promotes CD8⁺ T cell accumulation in the gut, while tampering with autophagy and glutathione negatively impacts the T cell pool. Thus, a PGE₂-autophagy-glutathione axis defines the metabolic adaptation of CD8⁺ T cells to the intestinal microenvironment, to ultimately influence the T cell pool.