Abstract
Nuclear receptor corepressor 1 (NCOR1) is a transcriptional regulator bridging repressive chromatin modifying enzymes with transcription factors. NCOR1 regulates many biological processes, however its role in T cells is not known. Here we show that Cd4-Cre-mediated deletion of NCOR1 (NCOR1 cKOCd4) resulted in a reduction of peripheral T cell numbers due to a decrease in single-positive (SP) thymocytes. In contrast, double-positive (DP) thymocyte numbers were not affected in the absence of NCOR1. The reduction in SP cells was due to diminished survival of NCOR1-null postselection TCRβhiCD69+ and mature TCRβhiCD69− thymocytes. NCOR1-null thymocytes expressed elevated levels of the pro-apoptotic factor BIM and showed a higher fraction of cleaved caspase 3-positive cells upon TCR stimulation ex vivo. However, staphylococcal enterotoxin B (SEB)-mediated deletion of Vβ8+ CD4SP thymocytes was normal, suggesting that negative selection is not altered in the absence of NCOR1. Finally, transgenic expression of the pro-survival protein BCL2 restored the population of CD69+ thymocytes in NCOR1 cKOCd4 mice to a similar percentage as observed in WT mice. Together, these data identify NCOR1 as a crucial regulator of the survival of SP thymocytes and revealed that NCOR1 is essential for the proper generation of the peripheral T cell pool.
Highlights
Resulted in a reduction of peripheral T cell numbers due to a decrease in single-positive (SP) thymocytes
In this study we provide genetic evidence that nuclear receptor corepressor 1 (NCOR1) is essential for the generation of the peripheral T cell pool by regulating the survival of positively selected TCRβhiCD69+/− thymocytes
Our data indicate an important role for NCOR1 beyond the DP stage, since there was a gradual decline of the percentages of NCOR1-null thymocytes from the CD69+ stage on during the DP to SP transition, which led to a significant reduction in cell numbers of TCRβhiCD69+/− cells
Summary
Resulted in a reduction of peripheral T cell numbers due to a decrease in single-positive (SP) thymocytes. Transgenic expression of the pro-survival protein BCL2 restored the population of CD69+ thymocytes in NCOR1 cKOCd4 mice to a similar percentage as observed in WT mice. Together, these data identify NCOR1 as a crucial regulator of the survival of SP thymocytes and revealed that NCOR1 is essential for the proper generation of the peripheral T cell pool. Chromatin modifying enzymes that regulate reversible changes in histone acetylation or methylation are recruited to gene-specific transcription factors as part of larger multiprotein complexes. This leads to either transcriptional activation or repression of target genes. Mouse models expressing mutant versions of NCOR1 revealed cell type- and tissue-specific functions for NCOR1 in muscle cells[8], adipocytes[9], macrophages[10] and in the liver[11]
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