title: Appropriate development of the liver Treg compartment is modulated by the microbiota and requires TGF-β and MyD88.
abstract: Neither the early postnatal development of the liver Treg compartment nor the factors that regulate its development has been characterized. We compared the early developmental patterns of Treg cell accumulation in murine liver, thymus, and spleen. A FoxP3(EGFP) reporter mouse was employed to identify Treg cells. Mononuclear cells were isolated from organs postnatally, stained for CD4, and examined by flow cytometry to enumerate FoxP3(+)CD4(hi) cells. To assess roles for TGF-β1, MyD88, and TLR2, gene-specific knockout pups were generated from heterozygous breeders. To test the role of commensal bacteria, pregnant dams were administered antibiotics during gestation and after parturition. The pattern of appearance of Treg cells differed in liver, spleen, and thymus. Notably, at 1-2 weeks, the frequency of CD4(hi) FoxP3(+) T cells in liver exceeded that in spleen by 1.5- to 2-fold. The relative increase in liver Treg frequency was transient and was dependent upon TGF-β1 and MyD88, but not TLR2, and was abrogated by antibiotic treatment. A relative increase in liver Treg frequency occurs approximately 1-2 weeks after parturition that appears to be driven by colonization of the intestine with commensal bacteria and is mediated by a pathway that requires TGF-β1 and MyD88, but not TLR2.
authors.affiliation: The Geisel School of Medicine at Dartmouth, Department of Microbiology and Immunology, DHMC, One Medical Center Drive, Lebanon, NH 03756, USA.
authors.forename: Ann
authors.identifier: 0000-0003-1847-6659
authors.initials: A
authors.lastname: Maria
authors.affiliation: The Geisel School of Medicine at Dartmouth, Department of Pathology, DHMC, One Medical Center Drive, Lebanon, NH 03756, USA.
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: English
authors.affiliation: The Geisel School of Medicine at Dartmouth, Department of Microbiology and Immunology, DHMC, One Medical Center Drive, Lebanon, NH 03756, USA ; The Geisel School of Medicine at Dartmouth, Department of Pathology, DHMC, One Medical Center Drive, Lebanon, NH 03756, USA.
authors.forename: James D
authors.initials: JD
authors.lastname: Gorham
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002452:Cell Count; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007422:Intestines / Q000276:immunology / Q000382:microbiology; D008099:Liver / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D064307:Microbiota / Q000276:immunology*; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D011247:Pregnancy; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism*; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016212:Transforming Growth Factor beta