title: T-cell-expressed proprotein convertase furin is essential for maintenance of peripheral immune tolerance.
abstract: Furin is one of seven proprotein convertase family members that promote proteolytic maturation of proproteins. It is induced in activated T cells and is reported to process a variety of substrates including the anti-inflammatory cytokine transforming growth factor (TGF)-beta1 (refs 2-4), but the non-redundant functions of furin versus other proprotein convertases in T cells are unclear. Here we show that conditional deletion of furin in T cells allowed for normal T-cell development but impaired the function of regulatory and effector T cells, which produced less TGF-beta1. Furin-deficient T regulatory (Treg) cells were less protective in a T-cell transfer colitis model and failed to induce Foxp3 in normal T cells. Additionally, furin-deficient effector cells were inherently over-active and were resistant to suppressive activity of wild-type Treg cells. Thus, our results indicate that furin is indispensable in maintaining peripheral tolerance, which is due, at least in part, to its non-redundant, essential function in regulating TGF-beta1 production. Targeting furin has emerged as a strategy in malignant and infectious disease. Our results suggest that inhibiting furin might activate immune responses, but may result in a breakdown in peripheral tolerance.
authors.affiliation: Molecular Immunology and Inflammation Branch, National Institute for Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. pesum@mail.nih.gov
authors.forename: Marko
authors.initials: M
authors.lastname: Pesu
authors.forename: Wendy T
authors.initials: WT
authors.lastname: Watford
authors.forename: Lai
authors.initials: L
authors.lastname: Wei
authors.forename: Lili
authors.initials: L
authors.lastname: Xu
authors.forename: Ivan
authors.initials: I
authors.lastname: Fuss
authors.forename: Warren
authors.initials: W
authors.lastname: Strober
authors.forename: John
authors.initials: J
authors.lastname: Andersson
authors.forename: Ethan M
authors.initials: EM
authors.lastname: Shevach
authors.forename: Martha
authors.initials: M
authors.lastname: Quezado
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bouladoux
authors.forename: Anton
authors.initials: A
authors.lastname: Roebroek
authors.forename: Yasmine
authors.initials: Y
authors.lastname: Belkaid
authors.forename: John
authors.initials: J
authors.lastname: Creemers
authors.forename: John J
authors.initials: JJ
authors.lastname: O'Shea
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology / Q000378:metabolism; D003092:Colitis / Q000276:immunology; D045683:Furin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D007108:Immune Tolerance / Q000276:immunology*; D007156:Immunologic Memory / Q000276:immunology; D039001:Integrin alpha Chains / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology* / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology
chemical_list: D015703:Antigens, CD; D015704:CD4 Antigens; D039001:Integrin alpha Chains; D053773:Transforming Growth Factor beta1; C091367:alpha E integrins; D045683:Furin