Journal
ISCIENCE
Volume 19, Issue -, Pages 996-+Publisher
CELL PRESS
DOI: 10.1016/j.isci.2019.08.024
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Funding
- DBT-JRF
- ILS fellowship
- DBT BINC fellowship
- DST-SNSF grant
- DST-SNSF [DST/INT/SWISS/SNSF/P-47/2015]
- DBT-India Ramalingaswami fellowship, SERB-India [EMR/2016/000717]
- DBT-India [BT/PR15908/MED/12/725/2016]
- HAO_SNF-Switzerland [310030_132492]
- Swiss National Science Foundation (SNF) [310030_132492] Funding Source: Swiss National Science Foundation (SNF)
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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-kappa B. NCoR1 knockdown (KD) reduced ReIA nuclear translocation and activity, whereas ReIB was unaffected, providing activated DCs a tolerogenic advantage. Moreover, NCoR1(DC-/-) 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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