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NCoR1: Putting the Brakes on the Dendritic Cell Immune Tolerance
Abdul Ahad1, Mathias Stevanin2, Shuchi Smita1
1Immuno-genomics & Systems Biology Laboratory, Institute of Life Sciences (ILS), Bhubaneswar, Odisha 751023, India; Manipal Academy of Higher Education, Manipal, Karnataka 576104, India.
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-κB. NCoR1 knockdown (KD) reduced RelA nuclear translocation and activity, whereas RelB was unaffected, providing activated DCs a tolerogenic advantage. Moreover, NCoR1DC-/- 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.
Insights
Nuclear receptor co-repressor 1 (NCoR1) in dendritic cells (DCs) is crucial for immune response. NCoR1 depletion promotes immune tolerance by upregulating tolerogenic genes, impacting regulatory T cell frequency and disease burden.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Dendritic cells (DCs) play a critical role in balancing immune responses.
- Fine-tuning the immunogenic versus tolerogenic nature of DCs is vital for therapeutic strategies.
- The precise mechanisms governing DC-mediated immune tolerance require further elucidation.
Purpose of the Study:
- To investigate the role of Nuclear Receptor Co-Repressor 1 (NCoR1) in regulating the immunogenic and tolerogenic programs of dendritic cells.
- To understand how NCoR1 influences the expression of tolerogenic genes and subsequent T cell responses.
- To explore the therapeutic potential of targeting NCoR1 in DC-mediated immune modulation.
Main Methods:
- Utilized NCoR1 knockdown (KD) models in dendritic cells.
- Analyzed gene expression profiles of tolerogenic genes in activated DCs.
- Investigated the binding of transcription factors, including PU.1 and nuclear factor-κB (NF-κB) subunits (RelA, RelB), to super-enhancers.
- Employed NCoR1 conditional knockout (DC-/-) mice and adoptive transfer experiments in models of bacterial and parasitic infections.
Main Results:
- NCoR1 directly represses the tolerogenic program in conventional DCs, essential for optimal immunogenic responses.
- NCoR1 depletion upregulated numerous tolerogenic genes in activated DCs, increasing FoxP3+ regulatory T cell (Treg) frequency.
- Mechanistically, NCoR1 masks PU.1-bound super-enhancers on tolerogenic genes, preventing subsequent NF-κB binding and RelA activity.
- NCoR1 deficiency in DCs led to enhanced Treg accumulation and increased disease severity in infected mice.
- Adoptive transfer of NCoR1 KD DCs mimicked these tolerogenic effects in vivo.
Conclusions:
- NCoR1 acts as a key repressor of DC-mediated immune tolerance.
- Targeting NCoR1 in DCs offers a promising strategy to control immune tolerance and potentially treat infectious diseases.
- Modulating NCoR1 function can shift the balance between immune activation and tolerance.
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