The gut microbiota promotes distal tissue regeneration via ROR?+ regulatory T cell emissaries [bulk RNA-seq]

Specific microbial signals induce the differentiation of a distinct pool of ROR?+ regulatory T cells (Tregs) crucial for intestinal homeostasis. We discovered highly analogous populations of microbiota-dependent Tregs that promote tissue regeneration at extra-gut sites, notably acutely injured skeletal muscle and fatty liver. Tissue damage elicited the emigration of ROR?+ Tregs from the gut to compromised tissues, wherein they regulated the dynamics and tenor of early inflammation and helped balance the proliferation versus differentiation of local stem cells. Reining in IL-17A-producing T cells was a major mechanism underlying these rheostatic functions. Our findings highlight the importance of gut-trained Treg emissaries in controlling the response to sterile injury of non-mucosal tissues. Overall design: To analyze the transcriptional differences between ROR?+ Tregs from the colon and regenerating muscle, Foxp3-Thy1.1x RorcGFP/wt male mice were injected with cardiotoxin, and 3 days later ROR?+ Tregs (CD4+TCRß+Foxp3Thy1.1+ROR?GFP+) were sorted from both tissues, and their transcriptional profiles were determined using RNA-seq. To assess the impact of ROR?+ Tregs on muscle regeneration, we analyzed the transcriptomes of whole muscle samples from Foxp3-cre x Maffl/fl (Maf?Treg) mice versus Foxp3-cre x Mafwt/wt (Maf-wt) littermate controls 7 days after cardiotoxin-induced muscle injury. For sorted muscle satellite cells, samples were analyzed from rIL-17A-treated mice against PBS-treated controls at 0, 1 and 3 days after cardiotoxin-induced muscle injury. To study the impact of ROR?+ Tregs on non-alcoholic steatohepatitis (NASH) development, we analyzed the transcriptomes of whole liver samples from Maf?Treg mice versus Maf-wt littermate controls 7 days after feeding them a choline-deficient, amino-acid-defined, high-fat diet (CDAHFD).