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

Matteo Villa (), David E. Sanin, Petya Apostolova, Mauro Corrado, Agnieszka M. Kabat, Carmine Cristinzio, Annamaria Regina, Gustavo E. Carrizo, Nisha Rana, Michal A. Stanczak, Francesc Baixauli, Katarzyna M. Grzes, Jovana Cupovic, Francesca Solagna, Alexandra Hackl, Anna-Maria Globig, Fabian Hässler, Daniel J. Puleston, Beth Kelly, Nina Cabezas-Wallscheid, Peter Hasselblatt, Bertram Bengsch, Robert Zeiser, Sagar, Joerg M. Buescher, Edward J. Pearce and Erika L. Pearce ()
Additional contact information
Matteo Villa: Max Planck Institute for Immunobiology and Epigenetics
David E. Sanin: Max Planck Institute for Immunobiology and Epigenetics
Petya Apostolova: Max Planck Institute for Immunobiology and Epigenetics
Mauro Corrado: Max Planck Institute for Immunobiology and Epigenetics
Agnieszka M. Kabat: Max Planck Institute for Immunobiology and Epigenetics
Carmine Cristinzio: Max Planck Institute for Immunobiology and Epigenetics
Annamaria Regina: Max Planck Institute for Immunobiology and Epigenetics
Gustavo E. Carrizo: Max Planck Institute for Immunobiology and Epigenetics
Nisha Rana: Max Planck Institute for Immunobiology and Epigenetics
Michal A. Stanczak: Max Planck Institute for Immunobiology and Epigenetics
Francesc Baixauli: Max Planck Institute for Immunobiology and Epigenetics
Katarzyna M. Grzes: Max Planck Institute for Immunobiology and Epigenetics
Jovana Cupovic: Max Planck Institute for Immunobiology and Epigenetics
Francesca Solagna: Max Planck Institute for Immunobiology and Epigenetics
Alexandra Hackl: Max Planck Institute for Immunobiology and Epigenetics
Anna-Maria Globig: University Medical Center Freiburg
Fabian Hässler: Max Planck Institute for Immunobiology and Epigenetics
Daniel J. Puleston: Max Planck Institute for Immunobiology and Epigenetics
Beth Kelly: Max Planck Institute for Immunobiology and Epigenetics
Nina Cabezas-Wallscheid: Max Planck Institute for Immunobiology and Epigenetics
Peter Hasselblatt: University Medical Center Freiburg
Bertram Bengsch: University Medical Center Freiburg
Robert Zeiser: University Medical Center Freiburg
Sagar: University Medical Center Freiburg
Joerg M. Buescher: Max Planck Institute for Immunobiology and Epigenetics
Edward J. Pearce: Max Planck Institute for Immunobiology and Epigenetics
Erika L. Pearce: Max Planck Institute for Immunobiology and Epigenetics

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-44689-2

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