title: Release of active TGF-β1 from the latent TGF-β1/GARP complex on T regulatory cells is mediated by integrin β8.
abstract: Activated T regulatory cells (Tregs) express latent TGF-β1 on their cell surface bound to GARP. Although integrins have been implicated in mediating the release of active TGF-β1 from the complex of latent TGF-β1 and latent TGF-β1 binding protein, their role in processing latent TGF-β1 from the latent TGF-β1/GARP complex is unclear. Mouse CD4(+)Foxp3(+) Treg, but not CD4(+)Foxp3(-) T cells, expressed integrin β8 (Itgb8) as detected by quantitative RT-PCR. Itgb8 expression was a marker of thymically derived (t)Treg, because it could not be detected on Foxp3(+)Helios(-) Tregs or on Foxp3(+) T cells induced in vitro. Tregs from Itgb8 conditional knockouts exhibited normal suppressor function in vitro and in vivo in a model of colitis but failed to provide TGF-β1 to drive Th17 or induced Treg differentiation in vitro. In addition, Itgb8 knockout Tregs expressed higher levels of latent TGF-β1 on their cell surface consistent with defective processing. Thus, integrin αvβ8 is a marker of tTregs and functions in a cell intrinsic manner in mediating the processing of latent TGF-β1 from the latent TGF-β1/GARP complex on the surface of tTregs.
authors.affiliation: Cellular Immunology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Justin P
authors.initials: JP
authors.lastname: Edwards
authors.affiliation: Cellular Immunology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Thornton
authors.affiliation: Cellular Immunology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 ESHEVACH@niaid.nih.gov.
authors.forename: Ethan M
authors.initials: EM
authors.lastname: Shevach
mesh_terms: D000818:Animals; D015415:Biomarkers; D002454:Cell Differentiation / Q000276:immunology; D003092:Colitis / Q000276:immunology; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D049452:Green Fluorescent Proteins / Q000235:genetics; D039641:Integrin beta Chains / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D016023:Integrins / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008565:Membrane Proteins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology; D014157:Transcription Factors / Q000096:biosynthesis; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D039641:Integrin beta Chains; D016023:Integrins; C484196:Lrrc32 protein, mouse; D008565:Membrane Proteins; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; C491746:Zfpn1a2 protein, mouse; C403414:integrin alphavbeta8; C094865:integrin beta8; D049452:Green Fluorescent Proteins