Prostaglandin E2controls the metabolic adaptation of T cells to the intestinal microenvironment

• DOI: 10.1101/2023.03.13.532431
• Publication Date: 2023-03-15T17:50:32Z
• Authors: 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-Wall...; Peter Hasselblatt; Bertram Bengsch; Robert Zeiser; Sagar; Joerg M. Buescher; Edward J Pearce; Erika L. Pearce
• Keywords: Science; Q; 610; Article

AbstractImmune cells must adapt to different environments during the course of an immune response. We studied the adaptation of CD8+T cells to the intestinal microenvironment and how this process shapes their residency in the gut. CD8+T cells progressively remodel their transcriptome and surface phenotype as they acquire gut residency, and downregulate expression of mitochondrial genes. Human and mouse gut-resident CD8+T cells have reduced mitochondrial mass, but maintain a viable energy balance to sustain their function. We found 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 PGE2sensing promotes CD8+T cell accumulation in the gut, while tampering with autophagy and glutathione negatively impacts the T cell population. 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.