NCoR1 restrains thymic negative selection by repressing Bim expression to spare thymocytes undergoing positive selection

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.

NCOR1—a new player on the field of T cell development

“…Wang et al. used the Lck ‐Cre (NCOR1‐cKO Lck ) as well as the Cd4 ‐Cre (NCOR1‐cKO Cd4 ) strains to delete NCOR1, whereas our laboratory used the Cd4 ‐Cre deleter strain . Both studies show that total thymocyte numbers are not significantly changed; however, the percentages as well as the numbers of SP thymocytes are reduced in NCOR1‐cKO Cd4 and NCOR1‐cKO Lck mice.…”

“…Rather, the expression of the pro‐apoptotic protein BIM that antagonizes the pro‐survival function of BCL‐2 in DP and SP thymocytes is dramatically increased in NCOR1‐cKO Cd4 and NCOR1‐cKO Lck mice. Further, in NCOR1‐ckO Lck mice, cleaved caspase 3‐positive DP thymocytes are enhanced by 2‐fold whereas there is no increase in the expression of the pro‐apoptotic factors FASL, TRAIL, TNF‐α, and BAK in activated or nonactivated DP thymocytes in vitro, indicating a role for NCOR1 specifically in controlling BIM‐dependent apoptosis. These findings also suggest that BIM‐mediated thymocyte apoptosis as well as accelerated BIM‐dependent negative selection contribute to the reduction of cells undergoing positive selection and increased cell death of SP thymocytes in the absence of NCOR1 .…”

“…As a consequence, this also leads to reduced numbers of peripheral T cells. Further, the generation of BM chimeric mice indicated that the reduction in the SP cell population is due to a T cell‐intrinsic defect . As described above, SP cells are generated from DP thymocytes in a process termed positive selection.…”

“…This defect is also not rescued by the expression of a transgenic MHC class II‐restricted ovalbumin‐specific OT‐II TCR, indicating that the impaired positive selection is not the result of defects in the recombination of TCR‐α and TCR‐β chains in the absence of NCOR1 . TCR signaling pathways are normal in NCOR1‐deficient thymocytes as evidenced by similar phosphorylation kinetics of PLC‐γ, ERK1/2, and p38 MAPK, as well as by comparable CD69 expression levels of WT and NCOR1‐cKO Lck thymocytes following TCR stimulation in vitro . Further, NCOR1‐deficient thymocytes up‐regulate also the expression of EGR2, CD127, and BCL‐2 during positive selection, which are key molecules that mediate the survival of DP cells during the progression toward the SP stage .…”

“…In humans, NCOR1 expression displays a broad tissue distribution, including brain, gastrointestinal tract, endocrine tissues, and reproductive organs (http://www.proteinatlas.org). A search in the ImmGen database (http://www.immgen.org) reveals that NCOR1 is also widely expressed in all immune cell lineages including T cells . NCOR1 is predominantly found in the nucleus; however, cytoplasmic localization of NCOR1 has been reported as well …”