| Autor: |
David NA; Center for Immunology, Masonic Cancer Center, Department of Laboratory Medicine and Pathology, Medical School, University of Minnesota, Minneapolis, MN 55455., Lee RD; Center for Immunology, Masonic Cancer Center, Department of Laboratory Medicine and Pathology, Medical School, University of Minnesota, Minneapolis, MN 55455., LaRue RS; Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN 55455., Joo S; Center for Immunology, Masonic Cancer Center, Department of Laboratory Medicine and Pathology, Medical School, University of Minnesota, Minneapolis, MN 55455., Farrar MA; Center for Immunology, Masonic Cancer Center, Department of Laboratory Medicine and Pathology, Medical School, University of Minnesota, Minneapolis, MN 55455. |
| Abstrakt: |
T cell development proceeds via discrete stages that require both gene induction and gene repression. Transcription factors direct gene repression by associating with corepressor complexes containing chromatin-remodeling enzymes; the corepressors NCOR1 and NCOR2 recruit histone deacetylases to these complexes to silence transcription of target genes. Earlier work identified the importance of NCOR1 in promoting the survival of positively-selected thymocytes. Here, we used flow cytometry and single-cell RNA sequencing to identify a broader role for NCOR1 and NCOR2 in regulating thymocyte development. Using Cd4-cre mice, we found that conditional deletion of NCOR2 had no effect on thymocyte development, whereas conditional deletion of NCOR1 had a modest effect. In contrast, Cd4-cre x Ncor1 f/f x Ncor2 f/f mice exhibited a significant block in thymocyte development at the DP to SP transition. Combined NCOR1/2 deletion resulted in increased signaling through the T cell receptor, ultimately resulting in elevated BIM expression and increased negative selection. The NF-κB, NUR77, and MAPK signaling pathways were also upregulated in the absence of NCOR1/2, contributing to altered CD4/CD8 lineage commitment, TCR rearrangement, and thymocyte emigration. Taken together, our data identify multiple critical roles for the combined action of NCOR1 and NCOR2 over the course of thymocyte development. |
