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. 2023 Jun 22;14:1183788. doi: 10.3389/fimmu.2023.1183788

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Copyright © 2023 Vietzen, Staber, Berger, Furlano, Kühner, Lubowitzki, Pichler, Strassl, Cornelissen and Puchhammer-Stöckl

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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HLA-E variants are associated with the development of EBV⁺ lymphomas and inhibit NKG2A⁺ NK cells. (A–D) Distribution of HLA-E variants in patients with (A) asymptomatic reactivations (N=96), (B) symptomatic reactivations (N=96), (C) EBV⁺HL (N=25), (D) EBV⁺nHL (N=38). Fractions represent the relative frequency of HLA-E*0101/0101, HLA-E*0101/0103 and HLA-E*0103/0103. ⁺ The frequency of the HLA-E variants was compared to the asymptomatic cohort by the Chi² Test. (E–G) Cell proliferation assays. (E) Enriched NKG2A⁺NKG2C^- NK cells were co-cultured with EBV-infected K562-CR2, K562-CR2-HLA-E*0103/0103 or K562-CR2-HLA-E*0101/0101 cells and were subsequently analyzed by flow-cytometry. (F) EBV-infected K562-CR2-HLA-E*0103/0103 or K562-CR2-HLA-E*0101/0101 cells or enriched NKG2A⁺NKG2C^- NK cells were co-cultured an LMP-1 peptide pool containing 300 µM of each of the LMP-1 peptide-derived GGDPHLPTL, GSDPHLPTL, GGDPHLPPL, GGDPPLPTL, GCDPHLPTL, GIDPHLPTL, GAGPHLPTL, GGDTPLPTL, GDDPHLPTL, GGDPHVPTL and GTDPHLPTL variants. Viable EBV-infected K562-CR2-HLA-E*0103/0103 or K562-CR2-HLA-E*0101/0101 cells or enriched NKG2A⁺NKG2C^- NK cells was subsequently analysed by flow-cytometry. (G) Enriched NKG2A⁺NKG2C^- NK cells were co-cultured with EBV-infected K562-CR2, K562-CR2-HLA-E*0103/0103 or K562-CR2-HLA-E*0101/0101 cells and 300µM of the positive control (VMAPRTLFL) or the LMP-1 derived GGDPHLPTL, GSDPHLPTL, GGDPHLPPL, GGDPPLPTL, GCDPHLPTL, GIDPHLPTL, GAGPHLPTL, GGDTPLPTL, GDDPHLPTL, GGDPHVPTL and GTDPHLPTL and were subsequently analysed by flow-cytometry. (H) Enriched NKG2A⁺NKG2C^- or NKG2A⁺NKG2C⁺ NK cells were co-cultured with EBV-infected K562-CR2, K562-CR2-HLA-E*0103/0103 or K562-CR2-HLA-E*0101/0101 cells and 300µM of the GGDPHLPTL variant and were subsequently analysed by flow-cytometry. For some experiments the α-NKG2A mAB 10µg/mL Monalizumab was added. (E–G) Plots represent the mean ( ± SD) of 12 independent replicates. RM one-way ANOVA (with the Geisser-Greenhouse correction) was used to compare the respective groups. p < 0.05 was considered significant. *p < 0.05; **p < 0.01; ***p < 0.001. EBV⁺HL, EBV⁺ Hodgkin lymphomas, EBV⁺nHL, EBV⁺ non-Hodgkin lymphomas, GrB, granzyme B, mAB, monoclonal antibody. Pos. Ctrl., positive control.