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: To further investigate the roles of Nr4a2 in Tregs we measured expression levels of Treg markers, activation status, cell death and proliferation in YFP+Foxp3+ and YFP–Foxp3+ Tregs in Nr4a2+/+Foxp3YFP-Cre/+ and Nr4a2fl/flFoxp3YFP-Cre/+ mice, which allowed us to compare Nr4a2-deficient and Nr4a2-suficient Tregs in the same mice. We observed decreased levels of Foxp3 and CD25 in YFP+ fraction in Nr4a2fl/flFoxp3YFP-Cre/+ mice (Fig. 7a). Other Treg markers such as CTLA-4 and GITR were expressed at a similar level between Nr4a2-deficient and Nr4a2-sufficient Tregs (Fig. 7a). A similar expression pattern of CD62L indicated equivalent activation status. A similar percentage of cells staining positive for Annexin V and Ki67 indicated an equivalent rate of cell proliferation and death between the Nr4a2-deficient and Nr4a2-sufficient Tregs, further supporting the notion that the insufficiency of the Nr4a2-deficient Tregs observed in Figure 6a,b was not caused by a difference in cell death or proliferation. We also compared the expression levels of Treg-relevant mRNA between Tregs from Nr4a2+/+Foxp3YFP-Cre and Nr4a2fl/flFoxp3YFP-Cre mice. We found decreased expression of Foxp3, indicating that the accelerated loss of Foxp3 in Nr4a2-deficient Tregs was at the mRNA level (Fig. 7b). For other genes, we observed a significant reduction of CD25, TGF-β1 and CCR9.
Affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan.