The activation trajectory of plasmacytoid dendritic cells in vivo during a viral infection

Abbas, Abdenour; Manh, Thien‐Phong Vu; Valente, Michael; Collinet, Nils; Attaf, Noudjoud; Dong, Chuang; Naciri, Karima; Chelbi, Rabie; Brelurut, Geoffray; Cervera-Marzal, Iñaki; Rauwel, Benjamin; Davignon, J.; Bessou, Gilles; Thomas‐Chollier, Morgane; Thieffry, Denis; Villani, Alexandra‐Chloé; Milpied, Pierre; Dalod, Marc; Tomasello, Elena

doi:10.1038/s41590-020-0731-4

Cited by 68 publications

(87 citation statements)

References 62 publications

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“…Our results showed that deletion of Zdhhc2 in mice dramatically decrease the activation level of all three subsets of T cells including αβ T cells, γδ T cells, and DETC in psoriatic skin. Our new findings in Zdhhc2 deficient mice that both IFN-α production and T cell activation were significantly inhibited, were consistent with results from previous studies showing that IFN-α produced by pDCs was critical to T cell activation ( 24 , 25 ). Other reports indicate that in vitiligo and systemic lupus erythematosus, IFN-α-producing pDCs were also exhibited accumulation in perilesional skin, leading to T cells activation and recruitment ( 36 – 38 ).…”

Section: Discussionsupporting

confidence: 92%

“…We reasoned that the blockade of pDC infiltration by Zdhhc2 deficiency in psoriatic skin could result in dampened T cell activity. Indeed a recent study showed that type I interferon producing pDCs were responsible for helper T cell activation ( 24 ). In addition, pDCs were found to drive γδ T cell activation through cytokine secretion such as IFN-α and TNF-α ( 25 ).…”

Section: Resultsmentioning

confidence: 99%

“…It has been reported that T cells also play an important role in the occurrence of psoriasis, and IFN-α produced by pDCs induces T cell activation ( 5 , 24 , 25 ). Our results showed that deletion of Zdhhc2 in mice dramatically decrease the activation level of all three subsets of T cells including αβ T cells, γδ T cells, and DETC in psoriatic skin.…”

Section: Discussionmentioning

confidence: 99%

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Zdhhc2 Is Essential for Plasmacytoid Dendritic Cells Mediated Inflammatory Response in Psoriasis

Zhou

Yang

et al. 2021

Front. Immunol.

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Zdhhc family genes are composed of 24 members that regulate palmitoylation, a post-translational modification process for proteins. Mutations in genes that alter palmitoylation or de-palmitoylation could result in neurodegenerative diseases and inflammatory disorders. In this study, we found that Zdhhc2 was robustly induced in psoriatic skin and loss of Zdhhc2 in mice by CRISPR/Cas9 dramatically inhibited pathology of the ear skin following imiquimod treatment. As psoriasis is an inflammatory disorder, we analyzed tissue infiltrating immune cells and cytokine production. Strikingly we found that a master psoriatic cytokine interferon-α (IFN-α) in the lesioned skin of wildtype (WT) mice was 23-fold higher than that in Zdhhc2 deficient counterparts. In addition, we found that CD45+ white blood cells (WBC) infiltrating in the skin of Zdhhc2 deficient mice were also significantly reduced. Amelioration in psoriasis and dramatically reduced inflammation of Zdhhc2 deficient mice led us to analyze the cellular components that were affected by loss of Zdhhc2. We found that imiquimod induced plasmacytoid dendritic cell (pDC) accumulation in psoriatic skin, spleen, and draining lymph nodes (DLN) were drastically decreased in Zdhhc2 deficient mice, and the expression of pDC activation marker CD80 also exhibited significantly inhibited in psoriatic skin. In further experiments, we confirmed the cell intrinsic effect of Zdhhc2 on pDCs as we found that loss of zDHHC2 in human CAL-1 pDC dampened both interferon regulatory factor 7 (IRF7) phosphorylation and IFN-α production. Therefore, we identified novel function of Zdhhc2 in controlling inflammatory response in psoriasis in mice and we also confirmed that crucial role of Zdhhc2 in pDCs by regulating IRF7 activity and production of the critical cytokine. Our results finding the dependence of IFN-α production on Zdhhc2 in inflamed murine skin and in human pDCs provide rationale for targeting this new molecule in treatment of inflammation.

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Section: Discussionsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Zdhhc2 Is Essential for Plasmacytoid Dendritic Cells Mediated Inflammatory Response in Psoriasis

Zhou

Yang

et al. 2021

Front. Immunol.

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“…cDCs can be further divided into cDC1 and cDC2, specialized in the activation of CD8 + and CD4 + T cells, respectively. pDCs are known for their capacity to produce large amounts of type I interferon (IFN-I) in response to viral infection followed by their conversion into cDC-like cells ( Abbas et al, 2020 ; Leylek and Idoyaga, 2019 ; Reizis, 2019 ). Advances in molecular profiling allowed the characterization of human blood DCs using single-cell RNA sequencing (scRNA-seq) ( See et al, 2017 ; Villani et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Chromatin Landscape Underpinning Human Dendritic Cell Heterogeneity

et al. 2020

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SUMMARY Human dendritic cells (DCs) comprise subsets with distinct phenotypic and functional characteristics, but the transcriptional programs that dictate their identity remain elusive. Here, we analyze global chromatin accessibility profiles across resting and stimulated human DC subsets by means of the assay for transposase-accessible chromatin using sequencing (ATAC-seq). We uncover specific regions of chromatin accessibility for each subset and transcriptional regulators of DC function. By comparing plasmacytoid DC responses to IFN-I-producing and non-IFN-I-producing conditions, we identify genetic programs related to their function. Finally, by intersecting chromatin accessibility with genome-wide association studies, we recognize DC subset-specific enrichment of heritability in autoimmune diseases. Our results unravel the basis of human DC subset heterogeneity and provide a framework for their analysis in disease pathogenesis.

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“…Marker genes of clusters for each dataset were extracted separately, using the FindMarkers function of Seurat and the "bimod" parameter. We then computed the Jaccard Indices (JI) between each cluster of one dataset with any other cluster of the other dataset, as already published (51). The JI measures similarity between finite sample sets, and is defined as the size of the intersection divided by the size of the union of the sample sets: J(A,B)= |A Ո B| / |A Ս B|.…”

Section: Alignment Of Clusters From Melanoma and Lung Adenocarcinoma mentioning

confidence: 99%

An NF-κB/IRF1 axis programs cDC1s to drive anti-tumor immunity

Ghislat

Cheema

Baudoin

et al. 2020

Preprint

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Conventional type 1 dendritic cells (cDC1s) are critical for anti-tumor immunity. They acquire antigens from dying tumor cells and cross-present them to CD8+ T cells, promoting the expansion of tumor-specific cytotoxic T cells. However, the signaling pathways that govern the anti-tumor functions of cDC1s are poorly understood. We mapped the molecular pathways regulating intra-tumoral cDC1 maturation using single cell RNA sequencing. We identified NF-κB and IFN pathways as being highly enriched in a subset of functionally mature cDC1s. The specific targeting of NF-κB or IFN pathways in cDC1s prevented the recruitment and activation of CD8+ T cells and the control of tumor growth. We identified an NF-κB-dependent IFNγ-regulated gene network in cDC1s, including cytokines and chemokines specialized in the recruitment and activation of cytotoxic T cells. We used single cell transcriptomes to map the trajectory of intra-tumoral cDC1 maturation which revealed the dynamic reprogramming of tumor-infiltrating cDC1s by NF-κB and IFN signaling pathways. This maturation process was perturbed by specific inactivation of either NF-κB or IRF1 in cDC1s, resulting in impaired expression of IFN-γ-responsive genes and consequently a failure to efficiently recruit and activate anti-tumoral CD8+ T cells. Finally, we demonstrate the relevance of these findings to cancer patients, showing that activation of the NF-κB/IRF1 axis in association with cDC1s is linked with improved clinical outcome. The NF-κB/IRF1 axis in cDC1s may therefore represent an important focal point for the development new diagnostic and therapeutic approaches to improve cancer immunotherapy.One Sentence SummaryNF-κB and IRF1 coordinate intra-tumoral cDC1 maturation and control of immunogenic tumor growth.

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The activation trajectory of plasmacytoid dendritic cells in vivo during a viral infection

Cited by 68 publications

References 62 publications

Zdhhc2 Is Essential for Plasmacytoid Dendritic Cells Mediated Inflammatory Response in Psoriasis

Zdhhc2 Is Essential for Plasmacytoid Dendritic Cells Mediated Inflammatory Response in Psoriasis

Chromatin Landscape Underpinning Human Dendritic Cell Heterogeneity

An NF-κB/IRF1 axis programs cDC1s to drive anti-tumor immunity

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