T cell maturation in the thymus requires both positive and negative selections. Positive selection has long been considered as a default process to allow the survival of thymocytes whose T cell receptors (TCR) display intermediate-affinity to self-peptide MHC complexes (self pMHC). In contrast, high affinity of TCRs to self pMHCs triggers negative selection of thymocytes to reinforce cell death through Bim-dependent apoptosis. However, how Bim is regulated downstream of the TCR signaling in the context of thymocyte selections is not well understood.
Dr. Qibin Leng’s laboratory at Institut Pasteur of Shanghai in collaboration with Dr. Ronald M Evans’s lab at Salk Institute for Biological Studies discovered that the survival of positively selecting thymocytes is, in fact, a tightly regulated process dependent on the Nuclear receptor Co-Repressor 1 (NCoR1). NCoR1 protects positively selecting thymocytes from negative selection, or programed cell death (apoptosis) by transcriptionally repressing Bim expression. NCoR1 represses Bim expression in thymocytes via binding to the Bim promoter and facilitating histone acetylation. In addition, strong TCR signaling promoted NCoR1 release from the Bim promoter to elicit Bim expression. Bim gene knockout rescued defective positive selection in NCoR-deficient mice. In conclusion, NCoR1 sets the transcriptional threshold to determine negative selection and positive selection in the thymus, thereby controlling the number of thymocytes to become mature T cells.
The article has been recently published an article in Nature Communications. The research work was supported by the National Natural Science Foundation of China, the Total Foundation and grants from NIH.