1. Molecular Immunology and Inflammation Branch, National Institute for Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
2. Mucosal Immunity Section, Laboratory of Host Defenses,
3. Cellular Immunology Section, Laboratory of Immunology
4. Mucosal Immunology Unit, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
5. Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
6. Experimental Mouse Genetics,
7. Laboratory for Biochemical Neuroendocrinology, K.U. Leuven and V.I.B., B-3000 Leuven, Belgium

Correspondence to: Marko Pesu¹ Correspondence and requests for materials should be addressed to M.P. (Email: pesum@mail.nih.gov).

Abstract

Furin is one of seven proprotein convertase family members that promote proteolytic maturation of proproteins¹. 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)-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-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-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.

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