Dengue virus replicon expressing the nonstructural proteins suffices to enhance membrane expression of HLA class I and inhibit lysis by human NK cells.
Many viruses escape the cellular immune response by downregulating cell surface expression of major histocompatibility complex (MHC) class I molecules. However, infection of cells with flaviviruses can upregulate the expression of these molecules. In this study we analyzed the expression of MHC class I in K562 and THP-1 human cell lines that were stably transfected with self-replicating subgenomic dengue virus RNA (replicons) and express all the dengue virus nonstructural proteins together. We show that MHC class I expression is upregulated in the dengue virus replicon-expressing cells and that the binding of natural killer (NK) inhibitory receptors to these cells is augmented. This upregulation results in reduced susceptibility of the dengue virus replicon-expressing cells to NK lysis, indicating a possible mechanism for evasion of the dengue virus from NK cell recognition. Visualizing MHC class I expression in replicon-containing K562 and THP-1 cells by confocal microscopy demonstrated aggregation of MHC class I molecules on the cell surface. Finally, replicon-expressing K562 cells manifested increased TAP (transporter associated with antigen processing) and LMP (low-molecular-mass protein) gene transcription, while replicon-expressing THP-1 cells manifested increased NF-kappaB activity and MHC class I transcription. We suggest that expression of dengue virus nonstructural proteins is sufficient to induce MHC class I upregulation through both TAP-dependent and -independent mechanisms. Additionally, aggregation of MHC class I molecules on the cell membrane also contributes to significantly higher binding of low-affinity NK inhibitory receptors, resulting in lower sensitivity to lysis by NK cells.
Shraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel.
Oren
O
Hershkovitz
Alon
A
Zilka
Ahuva
A
Bar-Ilan
Shai
S
Abutbul
Andrew
A
Davidson
Michela
M
Mazzon
Beate M
BM
Kümmerer
Alon
A
Monsoengo
Michael
M
Jacobs
Angel
A
Porgador
D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis; D002460:Cell Line; D002462:Cell Membrane / Q000737:chemistry; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic; D003716:Dengue Virus / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D018613:Microscopy, Confocal; D016328:NF-kappa B / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000276:immunology*
D018528:ATP-Binding Cassette Transporters; D015395:Histocompatibility Antigens Class I; D016328:NF-kappa B; D017361:Viral Nonstructural Proteins; C477327:transporter associated with antigen processing (TAP)