Microbial Programming of T-cell Migration from Gut to Brain

PROJECT SUMMARY The gut-brain axis is emerging as a central mediator of health and disease. Multiple studies have associated gut microbiota composition with neuroinflammatory and neurodegenerative diseases, and several recent studies suggest trafficking of immune cells from the gut to the brain. However, mechanistic understanding of how gut- educated T-cells get to the brain and why this axis exists at all are unclear. We recently discovered that CD4 T- cells are present in mouse and human brain and anatomically localize to the subfornical organ in the brain at steady state. In humans and mice, we performed deep transcriptional and functional profiling of CNS CD4 T- cells and found that they are Th1-like. Using mouse models, we found that CNS CD4-T-cell-derived IFN is required for CNS homeostasis by signaling to astrocytes. We found that CNS T-cells are derived from both the gut and also, surprisingly, the white adipose tissue, and can be phenotypically shaped by the states of both the gut microbiota composition and the state of the fat. Transcriptional and functional profiling across brain, white fat, and gut in mouse and humans identified potential mechanisms of how CD4 T-cells get from the gut to the brain. In this proposal, we will identify the mechanisms by which gut microbiota and the white fat control the CD4 T-cell compartment.