Abstract
Regulatory T cells (Tregs) play a major role in immune homeostasis and in the prevention of autoimmune diseases. It has been shown that c-Rel is critical in Treg thymic differentiation, but little is known on the role of NF-κB on mature Treg biology. We thus generated mice with a specific knockout of RelA, a key member of NF-κB, in Tregs. These mice developed a severe autoimmune syndrome with multi-organ immune infiltration and high activation of lymphoid and myeloid cells. Phenotypic and transcriptomic analyses showed that RelA is critical in the acquisition of the effector Treg state independently of surrounding inflammatory environment. Unexpectedly, RelA-deficient Tregs also displayed reduced stability and cells that had lost Foxp3 produced inflammatory cytokines. Overall, we show that RelA is critical for Treg biology as it promotes both the generation of their effector phenotype and the maintenance of their identity.
Highlights
CD4+ CD25+ forkhead box protein 3 (Foxp3)+ regulatory T cells (Tregs) play a critical role in immune homeostasis and in the prevention of autoimmune diseases by regulating immune responses [1]
To assess the role of RelA in Treg biology, we generated Foxp3Cre Relalox mice that have a specific deletion of RelA in Tregs by crossing mice expressing CRE in Tregs with mice expressing a Rela floxed allele
From 5 to 10 weeks of age, Foxp3Cre Relalox mice developed a spontaneous disease characterized by localized alopecia and skin lesions, and reduced weight gain compared to Foxp3Cre control mice (Figures 1B,C)
Summary
CD4+ CD25+ Foxp3+ regulatory T cells (Tregs) play a critical role in immune homeostasis and in the prevention of autoimmune diseases by regulating immune responses [1]. Foxp plays a critical role in the differentiation, suppressive function and stability of Tregs, other transcription factors (TFs), some of which interacting with Foxp in multi-molecular complexes, are involved in different aspects of their biology. Some, such as c-Rel, are involved in Treg differentiation [2, 3]. Mice with a conditional KO of RelA in Tregs develop a severe and early spontaneous autoimmune syndrome that is associated with a defect of effector Tregs [28,29,30] We confirmed these latter findings and added further information on the nature of the disease with extensive description of lymphoid and myeloid cell activation in lymphoid and non-lymphoid tissues. We revealed that RelA-deficient Tregs were unstable, lost Foxp expression and produced inflammatory cytokines, highlighting that RelA is critical to maintain Treg stability and identity
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