Prostaglandin E2 controls the metabolic adaptation of T cells to the intestinal microenvironment [RNA-seq]

Immune cells must adapt to different environments during an immune response. We studied the adaptation of CD8+ T cells to the intestinal microenvironment and how this process shapes tissue resident CD8+ T cells (TRM) in the gut. CD8+ T cells progressively remodel their transcriptome and surface phenotype as they acquire gut residency, and downregulate mitochondrial gene expression. Human and mouse gut-resident CD8+ T cells have reduced mitochondrial mass, but maintain a viable energy balance to sustain function. We found that the intestinal microenvironment is rich in prostaglandin E2 (PGE2), which drives mitochondrial depolarization in CD8+ T cells. Consequently, they engage autophagy to clear depolarized mitochondria, and enhance glutathione synthesis to scavenge reactive oxygen species (ROS). Impairing PGE2 sensing promotes TRM accumulation, while tampering with autophagy and glutathione negatively impacts the TRM pool. Thus, a PGE2-autophagy-glutathione axis defines the metabolic adaptation of CD8+ T cells to the intestinal microenvironment, to ultimately influence the TRM pool. Overall design: We targeted 7 groups of CD8 T cells: mesenteric lymph node Naive (1), central memory (2), effector memory (3) and resident memory (4); Small instestine Lamina propria effector memory (5) and resident memory (6); Small intestine intraepithelial lymphocytes effector memory (7). 10^5 cells per target population from each of 3 biological replicates were isolated, processed and analyzed.