T-cell-expressed proprotein convertase furin is essential for maintenance of peripheral immune tolerance
Pesu, Marko × Watford, Wendy T Wei, Lai Xu, Lili Fuss, Ivan Strober, Warren Andersson, John Shevach, Ethan M Quezado, Martha Bouladoux, Nicolas Roebroek, Anton Belkaid, Yasmine Creemers, John O'Shea, John J #
Nature publishing group
Nature vol:455 issue:7210 pages:246-250
Furin is one of seven proprotein convertase family members that promote proteolytic maturation of proproteins(1). 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)-beta 1 ( 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-beta 1. Furin-deficient T regulatory (T-reg) 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 T-reg 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-beta 1 production. Targeting furin has emerged as a strategy in malignant and infectious disease(5,6). Our results suggest that inhibiting furin might activate immune responses, but may result in a breakdown in peripheral tolerance.