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

Ahad, Abdul; Smita, Shuchi; Mishra, Gyan Prakash; Biswas, Viplov Kumar; Sen, Kaushik; Gupta, Bhawna; Garcin, Dominique; Acha‐Orbea, Hans; Raghav, Sunil K.

doi:10.1002/eji.202048566

Cited by 8 publications

(11 citation statements)

References 78 publications

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“…However, further studies are needed to clearly identify these functions. [1351,1399,1429,1430]. While all cDCs express high levels of CD11c and MHCII across tissues, pDCs are rather CD11c int cells that are characterized by the expression of markers such as SiglecH, B220 and mPDCA-1, while lacking expression of CD11b.…”

Section: Key Information Human Vs Murine This Is Detailed Inmentioning

confidence: 99%

Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition)

et al. 2021

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The third edition of Flow Cytometry Guidelines provides the key aspects to consider when performing flow cytometry experiments and includes comprehensive sections describing phenotypes and functional assays of all major human and murine immune cell subsets. Notably, the Guidelines contain helpful tables highlighting phenotypes and key differences between human and murine cells. Another useful feature of this edition is the flow cytometry analysis of clinical samples with examples of flow cytometry applications in the context of autoimmune diseases, cancers as well as acute and chronic infectious diseases. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid. All sections are written and peer-reviewed by leading flow cytometry experts and immunologists, making this edition an essential and state-of-the-art handbook for basic and clinical researchers.

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Section: Key Information Human Vs Murine This Is Detailed Inmentioning

confidence: 99%

Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition)

et al. 2021

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“…We recently reported that NCoR1 acts as a direct repressor of tolerogenic and antiviral immune response genes upon TLR9 ligation in cDC1 [ 33 , 34 ]. TLR9 activated NCoR1 depleted cDC1 showed increased Il10 and Ifnb1 gene expression.…”

Section: Resultsmentioning

confidence: 99%

“…NCoR1/SMRT were originally identified in complex of unliganded thyroid receptor and retinoic acid receptor and were thought to mediate their repression activity with only nuclear receptors but later several studies have shown the repression through other transcription factors such as BCL6, Kaiso, FOXP1 [ 29 – 32 ]. We have reported in our previous studies that perturbation of NCoR1 in cDC1s leads to derepression exemplified by increase in expression of proinflammatory cytokines, anti-inflammatory cytokines as well as antiviral response genes upon TLR9 activation [ 33 , 34 ]. This suggests that NCoR1 mediated strong repression of genes under TLR activation is required to mount signal specific immune response.…”

Section: Introductionmentioning

confidence: 99%

Epigenomics of conventional type-I dendritic cells depicted preferential control of TLR9 versus TLR3 response by NCoR1 through differential IRF3 activation

Mishra

Jha

Ahad

et al. 2022

Cell. Mol. Life Sci.

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Tight control of gene regulation in dendritic cells (DCs) is important to mount pathogen specific immune responses. Apart from transcription factor binding, dynamic regulation of enhancer activity through global transcriptional repressors like Nuclear Receptor Co-repressor 1 (NCoR1) plays a major role in fine-tuning of DC responses. However, how NCoR1 regulates enhancer activity and gene expression in individual or multiple Toll-like receptor (TLR) activation in DCs is largely unknown. In this study, we did a comprehensive epigenomic analysis of murine conventional type-I DCs (cDC1) across different TLR ligation conditions. We profiled gene expression changes along with H3K27ac active enhancers and NCoR1 binding in the TLR9, TLR3 and combined TLR9 + TLR3 activated cDC1. We observed spatio-temporal activity of TLR9 and TLR3 specific enhancers regulating signal specific target genes. Interestingly, we found that NCoR1 differentially controls the TLR9 and TLR3-specific responses. NCoR1 depletion specifically enhanced TLR9 responses as evident from increased enhancer activity as well as TLR9-specific gene expression, whereas TLR3-mediated antiviral response genes were negatively regulated. We validated that NCoR1 KD cDC1 showed significantly decreased TLR3 specific antiviral responses through decreased IRF3 activation. In addition, decreased IRF3 binding was observed at selected ISGs leading to their decreased expression upon NCoR1 depletion. Consequently, the NCoR1 depleted cDC1 showed reduced Sendai Virus (SeV) clearance and cytotoxic potential of CD8+ T cells upon TLR3 activation. NCoR1 directly controls the majority of these TLR specific enhancer activity and the gene expression. Overall, for the first time, we revealed NCoR1 mediates transcriptional control towards TLR9 as compared to TLR3 in cDC1. Graphical abstract

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“…Stable KD of Zbtb10 in cDC1 Mutu-DC line was generated using a lentivirus-mediated approach [45]. In brief, Lentiviral particle expressing shRNA transfer plasmid specific for Zbtb10 and empty vector (control shRNA) along with packaging plasmids (pCMVR8.74 and pMD2G) were produced in human embryonic kidney (HEK)-293 cells using Calphos kit (Clone tech).…”

Section: Development Of Stable Kd Of Zbtb10 In Cdc1 Mutu-dc Linementioning

confidence: 99%

Zbtb10 transcription factor is crucial for murine cDC1 activation and cytokine secretion

et al. 2021

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Dendritic cell (DC) activation and cytokine production is tightly regulated. In this study, we found that Zbtb10 expression is activation dependent and it is essential for the immunogenic function of cDC1. Zbtb10 knockdown (KD) significantly reduced the expression of co-stimulatory genes CD80 and CD86 along with cytokines including IL-12, IL-6, and IL-10, in activated cDC1 Mutu-DC line. Consequently, the clonal expansion of CD44 + effector T cells in co-cultured CD4 + T cells was drastically reduced owing to significantly reduced IL-2. At the same time, these CD44 + effector T cells were unable to differentiate toward Tbet + IFNγ + Th1 subtype. Instead, an increased frequency of Th2 cells expressing GATA3 + and IL-13 + was observed. Interestingly, in Zbtb10 KD condition the co-cultured T cells depicted increased expression of PD1 and LAG3, the T-cell anergic markers. Moreover, the global transcriptome analysis identified that Zbtb10 is pertinent for DC activation and its depletion in cDC1 completely shuts down their immune responses. Mechanistic analysis revealed that Zbtb10 KD enhanced the expression of NKRF (NF-κB repressing factor) leading to drastic suppression of NF-κB related genes. Zbtb10 KD abrogated p65 and RelB nuclear translocation, thereby controlling the activation and maturation of cDC1 and the ensuing adaptive T cell responses.

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

Cited by 8 publications

References 78 publications

Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition)

Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition)

Epigenomics of conventional type-I dendritic cells depicted preferential control of TLR9 versus TLR3 response by NCoR1 through differential IRF3 activation

Zbtb10 transcription factor is crucial for murine cDC1 activation and cytokine secretion

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