Abstract
Thymocytes must pass both positive and negative selections to become mature T cells. Negative selection purges thymocytes whose T-cell receptors (TCR) exhibit high affinity to self-peptide MHC complexes (self pMHC) to avoid autoimmune diseases, while positive selection ensures the survival and maturation of thymocytes whose TCRs display intermediate affinity to self pMHCs for effective immunity, but whether transcriptional regulation helps conserve positively selected thymocytes from being purged by negative selection remains unclear. Here we show that the specific deletion of nuclear receptor co-repressor 1 (NCoR1) in T cells causes excessive negative selection to reduce mature thymocyte numbers. Mechanistically, NCoR1 protects positively selected thymocytes from negative selection by suppressing Bim expression. Our study demonstrates a critical function of NCoR1 in coordinated positive and negative selections in the thymus.
Highlights
Thymocytes must pass both positive and negative selections to become mature T cells
We find that nuclear receptor co-repressor 1 (NCoR1) deficiency impacts positive selection by inducing apoptosis in activated thymocytes, resulting in reduced mature T cells in the thymus and periphery of NCoR1-deficient mice
Our results showed that the thymi of reconstituted mice with NCoR1-deficient OT-II bone marrow (BM) cells had an ~4-fold reduction in the number of CD4 SP and T-cell receptors (TCR) Vα2+ thymocytes respectively compared with WT (Fig. 4d, e)
Summary
Thymocytes must pass both positive and negative selections to become mature T cells. Negative selection purges thymocytes whose T-cell receptors (TCR) exhibit high affinity to self-peptide MHC complexes (self pMHC) to avoid autoimmune diseases, while positive selection ensures the survival and maturation of thymocytes whose TCRs display intermediate affinity to self pMHCs for effective immunity, but whether transcriptional regulation helps conserve positively selected thymocytes from being purged by negative selection remains unclear. NCoR1 protects positively selected thymocytes from negative selection by suppressing Bim expression. Positive selection occurs when thymocytes express TCRs with intermediate affinity to self-peptide MHC complexes (self pMHC) that are presented on cortical thymic antigen-presenting cells. Negative selection eliminates CD4+CD8+ double-positive (DP) or SP thymocytes expressing TCRs with high affinity to self pMHCs3. How NCoR1 regulates thymocyte development at later stages, during positive and negative selection, remains unknown. We find that NCoR1 deficiency impacts positive selection by inducing apoptosis in activated thymocytes, resulting in reduced mature T cells in the thymus and periphery of NCoR1-deficient mice. Bim-knockout rescues the thymocyte developmental defect in NCoR1-deficient mice, suggesting that Bim may be involved in this positive selection defect. Our data reveal a transcriptional mechanism that protects thymocytes with ongoing positive selection from negative selection, and further suggest that NCoR1 is essential for efficient thymocyte development and optimal peripheral T-cell homeostasis
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