T-cell-expressed proprotein convertase furin is essential for maintenance of peripheral immune tolerance.
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.
Pesu
Marko
M
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
Watford
Wendy T
WT
Wei
Lai
L
Xu
Lili
L
Fuss
Ivan
I
Strober
Warren
W
Andersson
John
J
Shevach
Ethan M
EM
Quezado
Martha
M
Bouladoux
Nicolas
N
Roebroek
Anton
A
Belkaid
Yasmine
Y
Creemers
John
J
O'Shea
John J
JJ
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
D015703:Antigens, CD; D015704:CD4 Antigens; D039001:Integrin alpha Chains; D053773:Transforming Growth Factor beta1; C091367:alpha E integrins; D045683:Furin