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  • Title: Nrf2 expression driven by Foxp3 specific deletion of Keap1 results in loss of immune tolerance in mice.
    Author: Klemm P, Rajendiran A, Fragoulis A, Wruck C, Schippers A, Wagner N, Bopp T, Tenbrock K, Ohl K.
    Journal: Eur J Immunol; 2020 Apr; 50(4):515-524. PubMed ID: 31840803.
    Abstract:
    The transcription factor Nrf2 regulates oxidative stress responses. However, the specific function of Nrf2 in Tregs, the central regulators of immune homeostasis, is unclear. Here, we report an unexpected but important role of Nrf2 in Tregs. Nrf2 expression driven by Foxp3 specific deletion of Keap1 resulted in an autoinflammatory phenotype with enhanced effector T cell activation and immune cell infiltrates in the lung. While early postnatal death of mice with Foxp3 specific deletion of Keap1 was most probably due to ectopic Foxp3cre expression and subsequent Keap1 deletion in epithelial cells, bone marrow chimeras suggest that Nrf2 activation intrinsically in Tregs contributes to a loss of Treg cells and diminished peripheral tolerance. Moreover, Nrf2 activation was associated with a loss of Foxp3 expression, but an enhanced glucose uptake and mTOR activity in Tregs, thus mimicking a metabolic phenotype that is associated with impaired lineage stability and cell functioning.
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