HLA Upregulation During Dengue Virus Infection Suppresses the Natural Killer Cell Response

Abstract

Dengue virus (DENV) is the most prevalent mosquito-borne virus in the world and a major cause of morbidity in the tropics and subtropics. Upregulation of HLA class I molecules has long been considered a feature of DENV infection, yet this has not been evaluated in the setting of natural infection. Natural killer (NK) cells, an innate immune cell subset critical for mounting an early response to viral infection, are inhibited by self HLA class I, suggesting that upregulation of HLA class I during DENV infection could dampen the NK cell response. Here we addressed whether upregulation of HLA class I molecules occurs during in vivo DENV infection and, if so, whether this suppresses the NK cell response. We found that HLA class I expression was indeed upregulated during acute DENV infection across multiple cell lineages in vivo . To better understand the role of HLA class I upregulation, we infected primary human monocytes, a major target of DENV infection, in vitro . Upregulation of total HLA class I is dependent on active viral replication and is mediated in part by cytokines and other soluble factors induced by infection, while upregulation of HLA-E occurs in the presence of replication-incompetent virus. Importantly, blocking DENV-infected monocytes with a pan-HLA class I Fab nearly doubles the frequency of degranulating NK cells, while blocking HLA-E does not significantly improve the NK cell response. These findings demonstrate that upregulation of HLA class I during DENV infection suppresses the NK cell response, potentially contributing to disease pathogenesis.

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

“…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 TNF‐α specifically, and did not mediate degranulation, in accordance with data previously observed with ex vivo NK cells of infected patients ; this is possibly explained by the upregulation of MHC class‐1 molecules, and HLA‐E in DENV‐2 infection, confirmed herein and previously described . However, we cannot exclude that the cytotoxic functions of NK cells are modulated differently in the function of the DENV serotype.…”

“…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.…”

Deiminated proteins and extracellular vesicles as novel biomarkers in pinnipeds: Grey seal (Halichoerus gryptus) and harbour seal (Phoca vitulina)

“…The major histocompatibility complex (MHC) is involved with both adaptive and innate immune systems, including via antigen processing and presentation, and is found in vertebrates throughout phylogeny [70]. Roles for MHC class I can also serve as an inhibitory ligand for natural killer cells and this mechanism can be exploited by viruses, which can inhibit various stages of the MHC class I antigen presentation pathway for immune evasion [71][72][73] as well as by some cancer cells, which can downregulate MHC I to avoid normal immune surveillance [74][75]. MHC I has been studied in harbour seal [76], with possible variation suggested in immune response genes in relation to susceptibility to phocine distemper virus [77] and with respect to morbillivirus infection in stranded cetaceans [78].…”

Characterization of the Impact of Daclizumab Beta on Circulating Natural Killer Cells by Mass Cytometry

“…NK cells were purified by magnetic bead isolation via negative selection (Miltenyi, cat. 130-092-657) and stained with the NK cell antibody panel ( Supplementary Table S1) as previously described (4,23,24). Cells were resuspended in 1x EQ Beads (Fluidigm) for normalization before acquisition on a Helios mass cytometer (Fluidigm).…”