title: The GARP/Latent TGF-β1 complex on Treg cells modulates the induction of peripherally derived Treg cells during oral tolerance.
abstract: Treg cells can secrete latent TGF-β1 (LTGF-β1), but can also utilize an alternative pathway for transport and expression of LTGF-β1 on the cell surface in which LTGF-β1 is coupled to a distinct LTGF-β binding protein termed glycoprotein A repetitions predominant (GARP)/LRRC32. The function of the GARP/LTGF-β1 complex has remained elusive. Here, we examine in vivo the roles of GARP and TGF-β1 in the induction of oral tolerance. When Foxp3(-) OT-II T cells were transferred to wild-type recipient mice followed by OVA feeding, the conversion of Foxp3(-) to Foxp3(+) OT-II cells was dependent on recipient Treg cells. Neutralization of IL-2 in the recipient mice also abrogated this conversion. The GARP/LTGF-β1 complex on recipient Treg cells, but not dendritic cell-derived TGF-β1, was required for efficient induction of Foxp3(+) T cells and for the suppression of delayed hypersensitivity. Expression of the integrin αvβ8 by Treg cells (or T cells) in the recipients was dispensable for induction of Foxp3 expression. Transient depletion of the bacterial flora enhanced the development of oral tolerance by expanding Treg cells with enhanced expression of the GARP/LTGF-β1 complex.
authors.affiliation: Cellular Immunology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Justin P
authors.initials: JP
authors.lastname: Edwards
authors.affiliation: Mucosal Immunology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Hand
authors.affiliation: Mucosal Immunology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Denise
authors.initials: D
authors.lastname: Morais da Fonseca
authors.affiliation: Cellular Immunology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Deborah D
authors.initials: DD
authors.lastname: Glass
authors.affiliation: Mucosal Immunology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Yasmine
authors.initials: Y
authors.lastname: Belkaid
authors.affiliation: Cellular Immunology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Ethan M
authors.initials: EM
authors.lastname: Shevach
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D015415:Biomarkers; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D000069196:Gastrointestinal Microbiome / Q000276:immunology; D015870:Gene Expression; D006968:Hypersensitivity, Delayed / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007108:Immune Tolerance / Q000235:genetics; D056747:Immunomodulation; D016130:Immunophenotyping; D016023:Integrins / Q000235:genetics / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D011485:Protein Binding; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D000941:Antigens; D015415:Biomarkers; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D016023:Integrins; D007376:Interleukin-2; C484196:Lrrc32 protein, mouse; D008565:Membrane Proteins; D053773:Transforming Growth Factor beta1; C403414:integrin alphavbeta8
keywords: Foxp3; GARP; TGF-β; Tolerance; Treg cell