Prostaglandin E controls the metabolic adaptation of T cells to the intestinal microenvironment.

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 E (PGE), 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 PGE sensing promotes CD8 T cell accumulation in the gut, while tampering with autophagy and glutathione negatively impacts the T cell pool. Thus, a PGE-autophagy-glutathione axis defines the metabolic adaptation of CD8 T cells to the intestinal microenvironment, to ultimately influence the T cell pool.