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 M L Widjaja, Christopher M. Harpur, Sue Lester, Jamie Rossjohn, Jeff Szer, Anthony Schwarer, Kenneth Bradstock, Peter G. Bardy, Maria Cristina Mingari, Lorenzo Moretta, Lucy C. Sullivan, Andrew G. Brooks

Research output: Contribution to journalArticlepeer-review

Abstract

Natural killer (NK) cell recognition of the nonclassical 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 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 analyzed UL40 sequences isolated from 32 hematopoietic stem cell transplantation recipients experiencing cytomegalovirus reactivation. The UL40 protein showed a "polymorphic hot spot" within the region that encodes the HLA leader sequence mimic. Although 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
Volume288
Issue number12
DOIs
Publication statusPublished - Mar 22 2013

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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