Few Foxp3+ regulatory T cells are sufficient to protect adult mice from lethal autoimmunity

Christian T. Mayer, Peyman Ghorbani, Anja A. Kühl, Philipp Stüve, Maike Hegemann, Luciana Berod, M. Eric Gershwin, Tim Sparwasser

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Foxp3 specifies the Treg cell lineage and is indispensable for immune tolerance. Accordingly, rare Foxp3 mutations cause lethal autoimmunity. The mechanisms precipitating more prevalent human autoimmune diseases are poorly understood, but involve a combination of genetic and environmental factors. Many autoimmune diseases associate with a partial Treg-cell dysfunction, yet mouse models reflecting such complex pathophysiological processes are rare. Around 95% of Foxp3+ Treg cells can be specifically depleted in bacterial artifical chromosome (BAC)-transgenic Depletion of REGulatory T cells (DEREG) mice through diphtheria toxin (DT) treatment. However, Treg-cell depletion fails to cause autoimmunity in adult DEREG mice for unclear reasons. By crossing Foxp3GFP knock-in mice to DEREG mice, we introduced additional genetic susceptibility that does not affect untreated mice. Strikingly, DT treatment of DEREG × Foxp3GFP mice rapidly causes autoimmunity characterized by blepharitis, tissue damage, and autoantibody production. This inflammatory disease is associated with augmented T-cell activation, increased Th2 cytokine production and myeloproliferation, and is caused by defective Treg-cell homeostasis, preventing few DT-insensitive Treg cells from repopulating the niche after Treg-cell depletion. Our study provides important insights into self-tolerance. We further highlight DEREG × Foxp3GFP mice as a model to investigate the role of environmental factors in precipitating autoimmunity. This may help to better understand and treat human autoimmunity.

Original languageEnglish (US)
Pages (from-to)2990-3002
Number of pages13
JournalEuropean Journal of Immunology
Volume44
Issue number10
DOIs
StatePublished - Oct 1 2014

Keywords

  • Autoimmunity
  • DEREG
  • Scurfy
  • Treg cells

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Medicine(all)

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    Mayer, C. T., Ghorbani, P., Kühl, A. A., Stüve, P., Hegemann, M., Berod, L., Gershwin, M. E., & Sparwasser, T. (2014). Few Foxp3+ regulatory T cells are sufficient to protect adult mice from lethal autoimmunity. European Journal of Immunology, 44(10), 2990-3002. https://doi.org/10.1002/eji.201344315