Journal Article

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

Wei, Lai, Quezado, Martha, Andersson, John, Pesu, Marko, Strober, Warren, Bouladoux, Nicolas, Creemers, John, Roebroek, Anton, Xu, Lili, Fuss, Ivan, O’Shea, John J., Shevach, Ethan M., Watford, Wendy T., Belkaid, Yasmine

2008

Overview

Furin's role in T cells 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 T reg 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 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)-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 (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-β1 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.

• Publisher: Nature Publishing Group UK,Nature Publishing,Nature Publishing Group
• Subject: Animals / Antigens, CD - immunology / Autoimmunity - immunology / Biological and medical sciences / CD4 Antigens - immunology / CD4 Antigens - metabolism / Colitis - immunology / Cystic fibrosis / Cytokines / Disease / Fundamental and applied biological sciences. Psychology / Fundamental immunology / Furin - deficiency / Furin - genetics / Furin - metabolism / Gene expression / Gene Expression Profiling / Humanities and Social Sciences / Immune system / Immune Tolerance - immunology / Immunobiology / Immunologic Memory - immunology / Immunological tolerance / Infectious diseases / Inflammatory bowel disease / Integrin alpha Chains - immunology / letter / Lymphocyte Activation - immunology / Mice / Mice, Inbred C57BL / multidisciplinary / Physiological aspects / Proteases / Science / Science (multidisciplinary) / Small intestine / T-Lymphocytes - cytology / T-Lymphocytes - enzymology / T-Lymphocytes - immunology / Thymus Gland - cytology / Thymus Gland - immunology / Transforming Growth Factor beta1 - biosynthesis / Transforming Growth Factor beta1 - genetics / Transforming Growth Factor beta1 - immunology / Transforming growth factors