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

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 Foxp3 GFP knock-in mice to DEREG mice, we introduced additional genetic susceptibility that does not affect untreated mice. Strikingly, DT treatment of DEREG × Foxp3 GFP 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 × Foxp3 GFP mice as a model to investigate the role of environmental factors in precipitating autoimmunity. This may help to better understand and treat human autoimmunity.Keywords: Autoimmunity r DEREG r Scurfy r Treg cellsAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionTreg cells play a principal role in mediating tolerance to selfantigens and both their lineage and function is specifically Correspondence: Dr. Tim Sparwasser e-mail: tim.sparwasser@twincore.de defined by the transcription factor Foxp3 [1][2][3][4][5][6]. Additionally, Treg cells can also negatively regulate appropriate responses against pathogens and tumor cells [7,8]. The scurfy mouse harbours a natural frameshift mutation in the Foxp3 gene resulting in a * These authors contributed equally to this work.C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2014. 44: 2990 Immunomodulation 2991 complete loss of Treg-cell function and lethal autoimmunity [9,10]. This mirrors the rare Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) syndrome in humans similarly caused by FOXP3 mutations [11]. Impaired Treg-cell function has also been implied in more frequent human autoimmune diseases such as type I diabetes, rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus [12]. However, the mechanisms precipitating and sustaining these prevalent diseases are much less understood and involve both genetic and environmental predisposing factors to varying degrees [13]. DT [19]. Surprisingly, adult DEREG mice show no observable signs of ...

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