Polymorphism in human cytomegalovirus UL40 impacts on recognition of human leukocyte antigen-E (HLA-E) by natural killer cells

Susan L Heatley, Gabriella Pietra, Jie Lin, Jacqueline ML Widjaja, Christopher M Harpur, Sue Lester, Jamie Rossjohn, Jeff Szer, A Schwarer, Kenneth F Bradstock, Peter Bardy, Maria Cristina Mingari, Lorenzo Moretta, Lucy C Sullivan, Andrew Brooks

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68 Citations (Scopus)


Natural Killer (NK) cell recognition of the non-classical Human Leukocyte Antigen (HLA) molecule HLA-E is dependent on the presentation of a nonamer peptide derived from the leader sequence of other HLA molecules to CD94-NKG2 receptors. However, human cytomegalovirus (CMV) can manipulate this central innate interaction through the provision of a mimic of the HLA-encoded peptide derived from the immunomodulatory glycoprotein UL40. Here we analysed UL40 sequences isolated from 32 hematopoietic stem cell transplantation (HSCT) recipients experiencing CMV reactivation. The UL40 protein showed a polymorphic hotspot within the region that encodes the HLA leader sequence mimic. While all sequences that were identical to those encoded within HLA-I genes permitted the interaction between HLA-E and CD94-NKG2 receptors, other UL40 polymorphisms reduced the affinity of the interaction between HLA-E and CD94-NKG2 receptors. Furthermore functional studies using NK cell clones expressing either the inhibitory receptor CD94-NKG2A or the activating receptor CD94-NKG2C identified UL40-encoded peptides that were capable of inhibiting target cell lysis via interaction with CD94-NKG2A, yet had little capacity to activate NK cells through CD94-NKG2C. The data suggest that UL40 polymorphisms may aid evasion of NK cell immunosurveillance by modulating the affinity of the interaction with CD94-NKG2 receptors.
Original languageEnglish
Pages (from-to)8679 - 8690
Number of pages12
JournalJournal of Biological Chemistry
Issue number12
Publication statusPublished - 2013

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