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NCoR1: Putting the Brakes on the Dendritic Cell Immune Tolerance

Abdul Ahad, Mathias Stevanin, Shuchi Smita, Gyan Prakash Mishra, Dheerendra Gupta, Sebastian Waszak, Uday Aditya Sarkar, Soumen Basak, Bhawna Gupta, Hans Acha-Orbea, Sunil Kumar Raghav
IScience 2019 August 17, 19: 996-1011
31522122
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.

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