ABSTRACT
How the microbiota modulate immune functions remains poorly understood. Mucosal-associated invariant T (MAIT) cells are implicated in mucosal homeostasis and absent in germ-free mice. Here, we show that commensal bacteria govern murine MAIT intrathymic development, as MAIT cells did not recirculate to the thymus. MAIT development required RibD expression in bacteria, indicating that production of the MAIT antigen 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU) was necessary. 5-OP-RU rapidly traveled from mucosal surfaces to the thymus, where it was captured by the major histocompatibility complex class Ib molecule MR1. This led to increased numbers of the earliest MAIT precursors and the expansion of more mature receptor-related, orphan receptor γt-positive MAIT cells. Thus, a microbiota-derived metabolite controls the development of mucosally targeted T cells in a process blurring the distinction between exogenous antigens and self-antigens.
Subject(s)
Gastrointestinal Microbiome , Mucosal-Associated Invariant T Cells/cytology , Mucous Membrane/immunology , Ribitol/analogs & derivatives , Thymus Gland/cytology , Uracil/analogs & derivatives , Animals , Escherichia coli , Escherichia coli Proteins , Germ-Free Life , Histocompatibility Antigens Class I/immunology , Lung/cytology , Mice , Mice, Inbred C57BL , Mice, Knockout , Minor Histocompatibility Antigens/immunology , Nucleotide Deaminases , Receptors, Antigen, T-Cell/immunology , Ribitol/immunology , Specific Pathogen-Free Organisms , Spleen/cytology , Sugar Alcohol Dehydrogenases , Symbiosis , Uracil/immunologyABSTRACT
The circadian clock and associated feeding rhythms have a profound impact on metabolism and the gut microbiome. To what extent microbiota reciprocally affect daily rhythms of physiology in the host remains elusive. Here, we analyzed transcriptome and metabolome profiles of male and female germ-free mice. While mRNA expression of circadian clock genes revealed subtle changes in liver, intestine, and white adipose tissue, germ-free mice showed considerably altered expression of genes associated with rhythmic physiology. Strikingly, the absence of the microbiome attenuated liver sexual dimorphism and sex-specific rhythmicity. The resulting feminization of male and masculinization of female germ-free animals is likely caused by altered sexual development and growth hormone secretion, associated with differential activation of xenobiotic receptors. This defines a novel mechanism by which the microbiome regulates host metabolism.
