Author:
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 ,Buescher Joerg M.,Pearce Edward J,Pearce Erika L.
Abstract
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.
Publisher
Cold Spring Harbor Laboratory