The nuclear orphan receptor Nr4a2 induces Foxp3 and regulates differentiation of CD4+ T cells.
Bottom Line: Regulatory T cells (Tregs) have a central role in maintaining immune homoeostasis through various mechanisms.Nr4a2 binds to regulatory regions of Foxp3, where it mediates permissive histone modifications.Nr4a2-deficeint Tregs are prone to lose Foxp3 expression and have attenuated suppressive ability both in vitro and in vivo.
Affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan.Show MeSH
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Mentions: The findings above suggest the involvement of Nr4a2 in Foxp3 induction and Th1 suppression. To analyse the roles of Nr4a2 in T-cell development and differentiation, we crossed Nr4a2-floxed mice with Lck-Cre+ mice, which express Cre-recombinase specifically in T cells3536. Although more than half of the Nr4a2fl/flLck-Cre+ mice died neonatally with unknown reasons, surviving mice developed normally and were fertile, and had no symptoms of autoimmune diseases up to 4 months of age. However, the population of CD44highCD62Llow-activated CD4+ T cells, as well as that of IFN-γ+ cells were significantly increased in Nr4a2fl/flLck-Cre+ mice compared with Nr4a2+/+Lck-Cre+ littermates. On the other hand, the number of Tregs in the thymus and spleen was not altered in the Nr4a2fl/flLck-Cre+ mice (Supplementary Fig. S5a,b). We isolated naïve CD4+ T cells from Nr4a2fl/flLck-Cre+ and Nr4a2+/+Lck-Cre+ mice, and cultured them under neutral, Th1-, Th17- and iTreg-skewing conditions. We observed strong induction of Th1 under all culture conditions, and a decrease in iTreg and Th17 induction (Fig. 5a). Expression levels of Foxp3 protein were also lower in Nr4a2-deficient iTreg cells (Fig. 5b). These results are consistent with forced expression studies, which indicate the involvement of Nr4a2 in Th1 repression and Foxp3 induction.
Affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan.