HLA upregulation during dengue virus infection suppresses the natural killer cell response

McKechnie, Julia L.; Beltran, Davis; Pitti, Arcelys; Sáenz, Lisseth; Araúz, Ana Belén; Vergara, Rosemary; Harris, Eva; Lanier, Lewis L.; Blish, Catherine A.; López‐Vergès, Sandra

doi:10.1101/698803

Cited by 4 publications

(11 citation statements)

References 34 publications

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“…In this study, we used an in vitro model of co-culture to analyze the cellular and molecular events required for the control of DENV-2 infection by NK cells. We demonstrated that infection of Mo-DCs by DENV-2 induced autologous NK cells to produce IFN-γ and TNFα specifically, and did not mediate degranulation, in accordance with data previously observed with ex vivo NK cells of infected patients [12][13][14]; this is possibly explained by the upregulation of MHC class-1 molecules, and HLA-E in DENV-2 infection, confirmed herein and previously described [26,27,32]. However, we cannot exclude that the cytotoxic functions of NK cells are modulated differently in the function of the DENV serotype.…”

Section: Discussionsupporting

confidence: 92%

“…4A), as described previously for different flaviviruses, and unlike many other viruses that down‐regulate MHC class‐1 expression on infected cells . Concomitantly, HLA‐E expression was significantly increased in DENV‐2‐infected cells, as described . Moreover, the frequency and surface‐expression of the MHC class‐1‐related chain (MIC)‐A and MIC‐B, two ligands of NKG2D, were significantly induced in DENV‐2‐infected Mo‐DCs ( p = 0.0015), but not in bystander Mo‐DCs, when compared to non‐infected cells (Fig.…”

Section: Resultssupporting

confidence: 73%

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Glycogen synthetase kinase 3 inhibition drives MIC‐A/B to promote cytokine production by human natural killer cells in Dengue virus type 2 infection

et al. 2019

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Dengue virus (DENV) is the most widespread arbovirus worldwide and is responsible for major outbreaks. The host's immune response plays a crucial role in controlling this infection but might also contribute to the promotion of viral spread and immunopathology. In response to DENV infection, NK cells preferentially produce cytokines and are cytotoxic in the presence of specific antibodies. Here, we identified that DENV‐2 inhibits glycogen synthase kinase 3 (GSK‐3) activity to subsequently induce MHC class‐1‐related chain (MIC) A and MIC‐B expression and IL‐12 production in monocyte‐derived DCs, independently of the STAT‐3 pathway. The inhibition of GSK‐3 by DENV‐2 or small molecules induced MIC‐A/B expression on monocyte‐derived DCs, resulting in autologous NK cells of a specific increase in IFN‐γ and TNF‐α production, in the absence of direct cytotoxicity. Together, these findings identified GSK‐3 as a regulator of MIC‐A/B expression and suggested its role in DENV‐2 infection to specifically induce cytokine production by NK cells.

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Section: Discussionsupporting

confidence: 92%

Section: Resultssupporting

confidence: 73%

Glycogen synthetase kinase 3 inhibition drives MIC‐A/B to promote cytokine production by human natural killer cells in Dengue virus type 2 infection

et al. 2019

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“…Some putative receptor-ligand interactions that may trigger an anti-DENV NK cell response, such as NKp44/E protein, KIR2DS2/NS3-HLA-C, and others have been reported (24)(25)(26). We and others have also shown that upregulation of HLA class I molecules by DENV-infected cells suppresses the NK cell response (27)(28)(29). Importantly, prior work investigating the role of NK cells during in vivo DENV infection has been limited to examining either pediatric or adult patients, but never both in parallel (20)(21)(22)(23)30).…”

Section: Introductionmentioning

confidence: 93%

“…Cells were stained for mass cytometry as previously described (29). Briefly, in-house conjugated antibodies were made using Maxpar X8 Antibody Labeling Kits (Fluidigm), while preconjugated antibodies were purchased from Fluidigm and Thermo Fisher Scientific.…”

Section: Mass Cytometry Staining Data Acquisition and Processingmentioning

confidence: 99%

“…In the CD14 -CD16 + subset there were six markers whose expression was significantly altered in adults ( Figure 4C). The markers whose expression was upregulated during DENV infection included Fas and HLA-E, whose role in suppressing the NK cell response to DENVinfected cells is currently unclear (29). In the pediatric CD14 -CD16 + myeloid cell subset there were 16 significant markers ( Figure 4D).…”

Section: Myeloid Cell Expression Of Ligands For Nk Cell Receptorsmentioning

confidence: 99%

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Mass cytometry analysis of the NK cell receptor-ligand repertoire reveals unique differences between dengue-infected children and adults

McKechnie

Beltran

Ferreira

et al. 2020

Preprint

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Dengue virus (DENV) is a significant cause of morbidity in many regions of the world, with children at the greatest risk of developing severe dengue. Natural killer (NK) cells, characterized by their ability to rapidly recognize and kill virally infected cells, are activated during acute DENV infection. However, their role in viral clearance versus pathogenesis has not been fully elucidated. Our goal was to profile the NK cell receptor-ligand repertoire to provide further insight into the function of NK cells during pediatric and adult DENV infection. We used mass cytometry (CyTOF) to phenotype isolated NK cells and peripheral blood mononuclear cells (PBMCs) from a cohort of DENV-infected children and adults. Using unsupervised clustering, we found that pediatric DENV infection leads to a decrease in total NK cell frequency with a reduction in the percentage of CD56dimCD38bright NK cells and an increase in the percentage of CD56dimperforinbright NK cells. No such changes were observed in adults. Next, we identified markers predictive of DENV infection using a differential state test. In adults, NK cell expression of activation markers, including CD69, perforin, and Fas-L, and myeloid cell expression of activating NK cell ligands, namely Fas, were predictive of infection. In contrast, NK cell expression of the maturation marker CD57 and increased myeloid cell expression of inhibitory ligands, such as HLA class I molecules, were predictive of pediatric DENV infection. These findings suggest that acute pediatric DENV infection may result in diminished NK cell activation, which could contribute to enhanced pathogenesis and disease severity.

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Natural killer cell responses to emerging viruses of zoonotic origin

Díaz-Salazar

Sun

2020

Current Opinion in Virology

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Highlights Emerging viruses avoid immune recognition by dampening early pro-inflammatory responses. Natural hosts of zoonotic viruses have developed enhanced interferon responses. NK cells are critical for early antiviral control but may contribute later to immunopathology. Viruses evade NK cell recognition by engaging inhibitory receptors and downregulating activating ligands. NK cells may contribute to protection through vaccination against zoonotic diseases.

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HLA upregulation during dengue virus infection suppresses the natural killer cell response

Cited by 4 publications

References 34 publications

Glycogen synthetase kinase 3 inhibition drives MIC‐A/B to promote cytokine production by human natural killer cells in Dengue virus type 2 infection

Glycogen synthetase kinase 3 inhibition drives MIC‐A/B to promote cytokine production by human natural killer cells in Dengue virus type 2 infection

Mass cytometry analysis of the NK cell receptor-ligand repertoire reveals unique differences between dengue-infected children and adults

Natural killer cell responses to emerging viruses of zoonotic origin

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