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 journalArticle

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

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HLA Antigens
Polymorphism
Cytomegalovirus
Natural Killer Cells
NK Cell Lectin-Like Receptor Subfamily C
NK Cell Lectin-Like Receptor Subfamily D
Peptides
Clone cells
Immunologic Monitoring
Molecules
Hematopoietic Stem Cell Transplantation
Protein Sorting Signals
Stem cells
Glycoproteins
Clone Cells
Genes

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Polymorphism in human cytomegalovirus UL40 impacts on recognition of human leukocyte antigen-E (HLA-E) by natural killer cells. / Heatley, Susan L.; Pietra, Gabriella; Lin, Jie; Widjaja, Jacqueline M L; Harpur, Christopher M.; Lester, Sue; Rossjohn, Jamie; Szer, Jeff; Schwarer, Anthony; Bradstock, Kenneth; Bardy, Peter G.; Mingari, Maria Cristina; Moretta, Lorenzo; Sullivan, Lucy C.; Brooks, Andrew G.

In: Journal of Biological Chemistry, Vol. 288, No. 12, 22.03.2013, p. 8679-8690.

Research output: Contribution to journalArticle

Heatley, SL, Pietra, G, Lin, J, Widjaja, JML, Harpur, CM, Lester, S, Rossjohn, J, Szer, J, Schwarer, A, Bradstock, K, Bardy, PG, Mingari, MC, Moretta, L, Sullivan, LC & Brooks, AG 2013, 'Polymorphism in human cytomegalovirus UL40 impacts on recognition of human leukocyte antigen-E (HLA-E) by natural killer cells', Journal of Biological Chemistry, vol. 288, no. 12, pp. 8679-8690. https://doi.org/10.1074/jbc.M112.409672
Heatley, Susan L. ; Pietra, Gabriella ; Lin, Jie ; Widjaja, Jacqueline M L ; Harpur, Christopher M. ; Lester, Sue ; Rossjohn, Jamie ; Szer, Jeff ; Schwarer, Anthony ; Bradstock, Kenneth ; Bardy, Peter G. ; Mingari, Maria Cristina ; Moretta, Lorenzo ; Sullivan, Lucy C. ; Brooks, Andrew G. / Polymorphism in human cytomegalovirus UL40 impacts on recognition of human leukocyte antigen-E (HLA-E) by natural killer cells. In: Journal of Biological Chemistry. 2013 ; Vol. 288, No. 12. pp. 8679-8690.
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