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.