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

Nature. 2008 Sep 11;455(7210):246-50. doi: 10.1038/nature07210.


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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / immunology
  • Autoimmunity / immunology
  • CD4 Antigens / immunology
  • CD4 Antigens / metabolism
  • Colitis / immunology
  • Furin / deficiency
  • Furin / genetics
  • Furin / metabolism*
  • Gene Expression Profiling
  • Immune Tolerance / immunology*
  • Immunologic Memory / immunology
  • Integrin alpha Chains / immunology
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Inbred C57BL
  • 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


  • Antigens, CD
  • CD4 Antigens
  • Integrin alpha Chains
  • Transforming Growth Factor beta1
  • alpha E integrins
  • Furin

Associated data

  • GEO/GSE11884