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- Title
T-cell-expressed proprotein convertase furin is essential for maintenance of peripheral immune tolerance.
- Authors
Pesu, Marko; Watford, Wendy T.; Lai Wei; Lili Xu; Fuss, Ivan; Strober, Warren; Andersson, John; Shevach, Ethan M.; Quezado, Martha; Bouladoux, Nicolas; Roebroek, Anton; Belkaid, Yasmine; Creemers, John; O'Shea, John J.
- 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)-β1 (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-β1. 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-β1 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.
- Subjects
T cells; CYTOKINES; TRANSFORMING growth factors; IMMUNOMODULATORS; IMMUNE response; CELLULAR immunity
- Publication
Nature, 2008, Vol 455, Issue 7210, p246
- ISSN
0028-0836
- Publication type
Article
- DOI
10.1038/nature07210