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Macrophage- and neutrophil-derived TNF-? instructs skin langerhans cells to prime antiviral immune responses.

ABSTRACT: Dendritic cells are major APCs that can efficiently prime immune responses. However, the roles of skin-resident Langerhans cells (LCs) in eliciting immune responses have not been fully understood. In this study, we demonstrate for the first time, to our knowledge, that LCs in cynomolgus macaque skin are capable of inducing antiviral-specific immune responses in vivo. Targeting HIV-Gag or influenza hemagglutinin Ags to skin LCs using recombinant fusion proteins of anti-Langerin Ab and Ags resulted in the induction of the viral Ag-specific responses. We further demonstrated that such Ag-specific immune responses elicited by skin LCs were greatly enhanced by TLR ligands, polyriboinosinic polyribocytidylic acid, and R848. These enhancements were not due to the direct actions of TLR ligands on LCs, but mainly dependent on TNF-? secreted from macrophages and neutrophils recruited to local tissues. Skin LC activation and migration out of the epidermis are associated with macrophage and neutrophil infiltration into the tissues. More importantly, blocking TNF-? abrogated the activation and migration of skin LCs. This study highlights that the cross-talk between innate immune cells in local tissues is an important component for the establishment of adaptive immunity. Understanding the importance of local immune networks will help us to design new and effective vaccines against microbial pathogens.

SUBMITTER: Epaulard O

PROVIDER: S-EPMC4134993 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Macrophage- and neutrophil-derived TNF-α instructs skin langerhans cells to prime antiviral immune responses.

Epaulard Olivier O Adam Lucille L Poux Candice C Zurawski Gerard G Salabert Nina N Rosenbaum Pierre P Dereuddre-Bosquet Nathalie N Zurawski Sandra S Flamar Anne-Laure AL Oh Sangkon S Romain Gabrielle G Chapon Catherine C Banchereau Jacques J Lévy Yves Y Le Grand Roger R Martinon Frédéric F

Journal of immunology (Baltimore, Md. : 1950) 20140723 5

Dendritic cells are major APCs that can efficiently prime immune responses. However, the roles of skin-resident Langerhans cells (LCs) in eliciting immune responses have not been fully understood. In this study, we demonstrate for the first time, to our knowledge, that LCs in cynomolgus macaque skin are capable of inducing antiviral-specific immune responses in vivo. Targeting HIV-Gag or influenza hemagglutinin Ags to skin LCs using recombinant fusion proteins of anti-Langerin Ab and Ags resulte ...[more]

PMID: 25057007

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Project description:Langerhans cells (LCs) are antigen presenting cells residing in the epidermis. Due to the difficulties with obtaining sufficient quantities of LCs for functional studies, many controversies exist about their origin and function. To gain insights into the molecular mechanisms underpinning LC biology and to elucidate how similar they are to a classical tissue resident DCs of myeloid origin, we undertook a whole transcriptome analysis of human skin migratory CD1a+ LCs and CD11c+ DDCs, stimulated with an epidermal pro-inflammatory cytokine, TNF-α over a time course of 24h. RNA was extracted from 250,000 human skin migratory CD1a+ LCs and CD11c+ DDCs stimulated in culture with 25ng/ml of TNF-α for 0, 2, 8 and 24h. RNA concentration and integrity was determined with an Agilent Bioanalyser (RIN of 7.0 or above) and gene expression analysis was carried out using the Human Genome U-219 Affymetrix platform by ARK-Genomics Centre, The Roslin Institute, Edinburgh. Expression data were normalised using the Robust Multichip Average (RMA) package. 2,334 transcripts regulated by exposure of skin DCs to TNF-α were identified with Bayesian Estimation of Temporal Regulation, a cut-off threshold 0.05 , for genes showing ≥ 1.5 fold difference between the maximum gene expression level and time 0 control in log2(x) RMA normalised gene expression. The interactive 3D diagram presenting the transcriptomic networks in human skin DCs can be viewed at: http://www.macrophages.com/LC_vs_DC RNA was extracted from 250,000 human skin migratory CD1a+ LCs and DDCs stimulated in culture with 25ng/ml of TNF-α for 0, 2, 8 and 24h. RNA concentration and integrity was determined with an Agilent Bioanalyser (RIN of 7.0 or above) and gene expression analysis was carried out using the Human Genome U-219 Affymetrix platform by ARK-Genomics Centre, The Roslin Institute, Edinburgh. Expression data were normalised using the Robust Multichip Average (RMA) package. 2,334 transcripts regulated by exposure of skin DCs to TNF-α were identified with Bayesian Estimation of Temporal Regulation, a cut-off threshold 0.05 , for genes showing ≥ 1.5 fold difference between the maximum gene expression level and time 0 control in log2(x) RMA normalised gene expression. *submitter cannot locate the CEL files

Dataset Information

Macrophage- and neutrophil-derived TNF-? instructs skin langerhans cells to prime antiviral immune responses.

Publications

Macrophage- and neutrophil-derived TNF-α instructs skin langerhans cells to prime antiviral immune responses.

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