Publication Date:
2008-08-15
Description:
Furin is one of seven proprotein convertase family members that promote proteolytic maturation of proproteins. 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)-beta1 (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-beta1. 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-beta1 production. Targeting furin has emerged as a strategy in malignant and infectious disease. Our results suggest that inhibiting furin might activate immune responses, but may result in a breakdown in peripheral tolerance.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2758057/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2758057/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉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 -- Z99 EY999999/Intramural NIH HHS/ -- England -- Nature. 2008 Sep 11;455(7210):246-50. doi: 10.1038/nature07210.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Immunology and Inflammation Branch, National Institute for Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. pesum@mail.nih.gov〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18701887" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Antigens, CD/immunology
;
Antigens, CD4/immunology/metabolism
;
Autoimmunity/immunology
;
Colitis/immunology
;
Furin/deficiency/genetics/*metabolism
;
Gene Expression Profiling
;
Immune Tolerance/*immunology
;
Immunologic Memory/immunology
;
Integrin alpha Chains/immunology
;
Lymphocyte Activation/immunology
;
Mice
;
Mice, Inbred C57BL
;
T-Lymphocytes/cytology/*enzymology/*immunology
;
Thymus Gland/cytology/immunology
;
Transforming Growth Factor beta1/biosynthesis/genetics/immunology
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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