T-cell-expressed proprotein convertase furin is essential for maintenance of peripheral immune tolerance

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Abstract
The protease furin is induced on T cell activation and is a target of Stat-transcription factors in T cells. Studying furin has been hampered by the fact that germline deletion of this gene is embryonically lethal. Here furin's physiological role in T cells is studied using a T cell-specific furin knockout mice. The striking finding is that conditional deletion of furin in T cells results in loss of peripheral tolerance and systemic autoimmune disease. Furin deficiency compromises TGF-β release and Treg function, and is associated with inherently more aggressive effector T cells. This research suggests that inhibiting furin may promote the immune response but may also cause the loss of peripheral tolerance by reducing levels of bioavailable TGF-β-1. Conditional knockout of the protease furin in CD4+ T cells is shown to result in impaired peripheral tolerance and autoimmune disease. Furin deficiency compromises TGF-β release and Treg function, and is associated with inherently more aggressive effector T cells. 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)-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 disease5,6. Our results suggest that inhibiting furin might activate immune responses, but may result in a breakdown in peripheral tolerance.