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

50 Citations (Scopus)

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.

LanguageEnglish
Pages8679-8690
Number of pages12
JournalJournal of Biological Chemistry
Volume288
Issue number12
DOIs
Publication statusPublished - 22 Mar 2013

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

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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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.",
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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

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

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AU - Heatley, Susan L.

AU - Pietra, Gabriella

AU - Lin, Jie

AU - Widjaja, Jacqueline M L

AU - Harpur, Christopher M.

AU - Lester, Sue

AU - Rossjohn, Jamie

AU - Szer, Jeff

AU - Schwarer, Anthony

AU - Bradstock, Kenneth

AU - Bardy, Peter G.

AU - Mingari, Maria Cristina

AU - Moretta, Lorenzo

AU - Sullivan, Lucy C.

AU - Brooks, Andrew G.

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