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

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)-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.

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Figure 1: Normal thymic T-cell development, but activated/memory phenotype of peripheral T cells in CD4cre-fur f/f mice.
Figure 2: Development of age-related autoimmunity in CD4cre-fur f/f mice.
Figure 3: Deletion of furin in T cells results in T-cell expansion/activation, and impairs TGF-β1 production and CD103 expression.
Figure 4: Furin deficiency results in increased T effector cell aggressiveness and impaired T regulatory cell protection in suppressing colitis.

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Gene Expression Omnibus

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The microarray files are deposited in Gene Expression Omnibus under accession number GSE11884.

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Acknowledgements

We thank J. Bonifacino (National Institute of Child Health and Human Development) and S. Wahl (National Institute of Dental and Craniofacial Research) for providing comments and reading the manuscript, A. Singer (National Cancer Institute) and L. Pobenzinsky (NCI) for providing suggestions, and M. Oukka (Harvard Medical School) for providing Foxp3-GFP mice. This work was supported by the Intramural Research Program of NIAMS, Academy of Finland, the Finnish Medical Foundation, the Maud Kuistila Memorial Foundation, the ‘Fonds voor Wetenschappelijk Onderzoek Vlaanderen’ and ‘Geconcerteerde Onderzoeksactie van de Vlaamse Gemeenschap’.

Author Contributions M.P. designed, performed and interpreted all the experiments and wrote the manuscript. W.T.W. helped to plan, perform and interpret suppression assays as well as some flow cytometry experiments. L.W. performed and interpreted the microarray experiments. L.X. helped to design and perform the TGF-β1 measurements. I.F. interpreted the data and analysed the gut histology. W.S. contributed to the experimental design of conversion and suppression assays and interpreted the data. J.A. helped to plan and perform the in vitro conversion assays. E.M.S. contributed to the experimental design of conversion and suppression assays and interpreted the data. M.Q. analysed histopathology. N.B. helped to isolate the gut lymphocytes. A.R. generated and provided the furf/+ animals. Y.B. provided the RAG2-/- and TCR-α-/- animals, contributed to the experimental design of conversion and suppression assays, and interpreted the data. J.C. generated and provided the furf/+ animals and helped to plan and interpret the experiments. J.J.O.’S. oversaw experimental designs, analysed and interpreted all acquired data, and wrote the manuscript.

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Correspondence to Marko Pesu.

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Pesu, M., Watford, W., Wei, L. et al. T-cell-expressed proprotein convertase furin is essential for maintenance of peripheral immune tolerance. Nature 455, 246–250 (2008). https://doi.org/10.1038/nature07210

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