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iScience. 2019 Sep 27;19:996-1011. doi: 10.1016/j.isci.2019.08.024. Epub 2019 Aug 17.

NCoR1: Putting the Brakes on the Dendritic Cell Immune Tolerance.

Author information

1
Immuno-genomics & Systems Biology Laboratory, Institute of Life Sciences (ILS), Bhubaneswar, Odisha 751023, India; Manipal Academy of Higher Education, Manipal, Karnataka 576104, India.
2
Department of Biochemistry CIIL, University of Lausanne (UNIL), Epalinges CH-1066, Switzerland.
3
Immuno-genomics & Systems Biology Laboratory, Institute of Life Sciences (ILS), Bhubaneswar, Odisha 751023, India; Department of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Bhubaneswar, Odisha 751024, India.
4
Immuno-genomics & Systems Biology Laboratory, Institute of Life Sciences (ILS), Bhubaneswar, Odisha 751023, India.
5
European Molecular Biology Laboratory (EMBL), Heidelberg 69117, Germany.
6
Systems Immunology Laboratory, National Institute of Immunology (NII), Aruna Asaf Ali Marg, New Delhi 110067, India.
7
Department of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Bhubaneswar, Odisha 751024, India.
8
Department of Biochemistry CIIL, University of Lausanne (UNIL), Epalinges CH-1066, Switzerland. Electronic address: hans.acha-orbea@unil.ch.
9
Immuno-genomics & Systems Biology Laboratory, Institute of Life Sciences (ILS), Bhubaneswar, Odisha 751023, India; Manipal Academy of Higher Education, Manipal, Karnataka 576104, India; Department of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Bhubaneswar, Odisha 751024, India. Electronic address: sunilraghav@ils.res.in.

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.

KEYWORDS:

Immune Response; Immunology; Molecular Mechanism of Gene Regulation; Transcriptomics

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