NR4A3 Mediates Thymic Negative Selection

Abstract Central tolerance aims to limit the production of T lymphocytes bearing TCR with high affinity for self-peptide presented by MHC molecules. The accumulation thymocytes such receptors is limited negative selection or diversion into alternative differentiation, including regulatory cell commitment. A role orphan nuclear receptor NR4A3 in has been suggested, but its function this process never investigated. We find that Nr4a3 transcription upregulated postselection double-positive thymocytes, particularly those have received a strong selecting signal and are destined selection. Indeed, we found an cells phenotype NR4A3-deficient mice as compared wild-type controls, suggesting transcriptional induction necessary self-reactive thymocytes. This consistent decrease cleaved caspase-3+–signaled more CD4+Foxp3−HELIOS+ thymus. further tested reconstituting transgenic expressing OVA Ag under control insulin promoter bone marrow from OT-I Nr4a3+/+ Nr4a3−/− mice. Accumulation autoreactive CD8 autoimmune diabetes developed only absence NR4A3. Overall, our results demonstrate important development.