NCoR1: Putting the Brakes on the Dendritic Cell Immune Tolerance

Abstract

Understanding the mechanisms fine-tuning immunogenic versus tolerogenic balance in dendritic cells (DCs) is of high importance for therapeutic approaches. We found that NCoR1-mediated direct repression of the tolerogenic program in conventional DCs is essential for induction of an optimal immunogenic response. NCoR1 depletion upregulated a wide variety of tolerogenic genes in activated DCs, which consequently resulted in increased frequency of FoxP3 + regulatory T cells. Mechanistically, NCoR1 masks the PU.1-bound super-enhancers on major tolerogenic genes after DC activation that are subsequently bound by nuclear factor-kB. NCoR1 knockdown (KD) reduced RelA nuclear translocation and activity, whereas RelB was unaffected, providing activated DCs a tolerogenic advantage. Moreover, NCoR1 DCÀ/mice depicted enhanced Tregs in draining lymph nodes with increased disease burden upon bacterial and parasitic infections. Besides, adoptive transfer of activated NCoR1 KD DCs in infected animals showed a similar phenotype. Collectively, our results demonstrated NCoR1 as a promising target to control DC-mediated immune tolerance.

NCOR1 Orchestrates Transcriptional Landscapes and Effector Functions of CD4+ T Cells

“…To investigate NCOR1 function in adult tissues and mice, conditional gene targeting approaches were performed as well as transgenic mouse models expressing mutant versions of NCOR1 were generated. These approaches demonstrated a key role for NCOR1 in the control of muscle physiology (11), in the regulation of adipocyte function (12,13), in liver metabolism (14), in macrophagemediated repression of atherosclerosis (15), and in dendritic cell-mediated regulation of immune tolerance (16). Collectively, these studies indicate that NCOR1 is an essential tissue-specific regulator of gene expression in mammals during development, differentiation, cell homeostasis, and metabolism (8).…”

Deregulated Immune Pathway Associated with Palbociclib Resistance in Preclinical Breast Cancer Models: Integrative Genomics and Transcriptomics

“…Previous studies have investigated NCOR1, MUC4, and MUC16 genes for their aberrant expression in various cancers and being attractive targets for immunotherapy [35,41,42]. NCOR1 has been found to have an important function in proper T cell development [43].…”

“…NCOR1 has been found to have an important function in proper T cell development [43]. Moreover, downregulation of NCOR1 in dendritic cells has been reported to induce FoxP3 + regulatory T cells by inhibiting Th17 cell development [35]. In addition, aberrant glycosylation of mucins interferes with the ability of natural killer cells to destroy tumor cells, suggesting immunosuppression around the tumor [32].…”

“…The association between mutated genes found only in palbociclib-resistant cells and CDK4/6 inhibitor resistance warrants further investigation. Among the four mutated genes described above (i.e., NCOR1, MUC16, MUC4, and RSPO2), NCOR1, MUC16, and MUC4 were reported to have been directly involved in modulating tumor microenvironment and thereby mediating drug resistance [33][34][35].…”

NCoR1 fine‐tunes type‐I IFN response in cDC1 dendritic cells by directly regulating Myd88‐IRF7 axis under TLR9

“…ChIP of NCoR1 in unstimulated and CpG-activated cDC1 line, its library preparation, and data processing has been described in detail recently [38]. In brief, cells were fixed.…”