Differential effects of US2, US6 and US11 human cytomegalovirus proteins on HLA class Ia and HLA-E expression: impact on target susceptibility to NK cell subsets.
We compared in an inducible expression system the individual effect of US2, US6 and US11 human cytomegalovirus (HCMV) proteins on HLA-E and HLA class Ia surface expression, assessing in parallel their influence on target susceptibility to NK cell clones. To this end, the RPMI 8866 B lymphoma cell line (HLA-A2, HLA-A3, HLA-B7, HLA-Cw7, HLA-E(R), HLA-E(G)) was stably cotransfected with the ecdysone receptor, together with the US sequences under the control of an ecdysone-inducible promoter. Biosynthesis of viral proteins was turned on by incubating transfectants with Ponasterone A. US6 down-regulated expression of all class I molecules, hampering target resistance to NK cell clones controlled by the CD94/NKG2A, KIR2DL2 and/or CD85j (ILT2 or LIR-1) inhibitory receptors. By contrast, US11 reduced the surface levels of class Ia molecules but preserved HLA-E; this rendered US11(+) cells sensitive to NK clones under the control of KIR2DL2 and/or CD85j, while their resistance to CD94/NKG2A(+)KIR2DL2(-) effector cells was maintained. US2 preserved as well HLA-E expression but selectively targeted class Ia molecules; in fact, HLA-A and HLA-C allotypes were down-modulated whereas HLA-B7 remained unaltered. US2(+) targets became sensitive to KIR2DL2(+) cells but remained resistant to CD94/NKG2A(+)CD85j(+) NK clones. The differential effects of US proteins on HLA class Ia and HLA-E likely reflect the evolutionary adaptation of HCMV to counteract NK-mediated surveillance.
D003602:Cytotoxicity, Immunologic; D006680:HLA Antigens / Q000032:analysis* / Q000235:genetics; D015789:HLA-A2 Antigen / Q000032:analysis; D015791:HLA-A3 Antigen / Q000032:analysis; D015793:HLA-B7 Antigen / Q000032:analysis; D015236:HLA-C Antigens / Q000032:analysis; D015395:Histocompatibility Antigens Class I / Q000032:analysis* / Q000235:genetics; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000502:physiology*; D016601:RNA-Binding Proteins / Q000502:physiology*; D014759:Viral Envelope Proteins; D014764:Viral Proteins / Q000502:physiology*; D000097625:HLA-E Antigens
D006680:HLA Antigens; D015789:HLA-A2 Antigen; D015791:HLA-A3 Antigen; D015793:HLA-B7 Antigen; D015236:HLA-C Antigens; D015395:Histocompatibility Antigens Class I; D008562:Membrane Glycoproteins; D016601:RNA-Binding Proteins; D014759:Viral Envelope Proteins; D014764:Viral Proteins; D000097625:HLA-E Antigens; C040178:HLA-C*70 antigen; C074546:US11 protein, herpesvirus; C118670:US2 protein, Varicellovirus; C432877:US6 protein, Human cytomegalovirus