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

J Biol Chem. 2013 Mar 22;288(12):8679-8690. doi: 10.1074/jbc.M112.409672. Epub 2013 Jan 18.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amino Acid Sequence
  • Binding Sites
  • Cells, Cultured
  • Cytomegalovirus / genetics*
  • Cytomegalovirus / immunology
  • Cytotoxicity, Immunologic
  • Female
  • HLA-E Antigens
  • Hematopoietic Stem Cell Transplantation
  • Histocompatibility Antigens Class I / chemistry
  • Histocompatibility Antigens Class I / metabolism*
  • Histocompatibility Antigens Class I / physiology
  • Humans
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Leukemia, Myeloid, Acute / therapy
  • Lymphoma, Non-Hodgkin / therapy
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • NK Cell Lectin-Like Receptor Subfamily C / metabolism
  • NK Cell Lectin-Like Receptor Subfamily D / metabolism
  • Phylogeny
  • Polymorphism, Genetic*
  • Protein Binding
  • Sequence Analysis, DNA
  • Viral Proteins / chemistry
  • Viral Proteins / genetics*
  • Viral Proteins / immunology
  • Young Adult

Substances

  • Histocompatibility Antigens Class I
  • KLRD1 protein, human
  • NK Cell Lectin-Like Receptor Subfamily C
  • NK Cell Lectin-Like Receptor Subfamily D
  • UL40 glycoprotein, Cytomegalovirus
  • Viral Proteins

Associated data

  • GENBANK/JQ060965
  • GENBANK/JQ060966
  • GENBANK/JQ060967
  • GENBANK/JQ060968
  • GENBANK/JQ060969
  • GENBANK/JQ060970
  • GENBANK/JQ060971
  • GENBANK/JQ060972
  • GENBANK/JQ060973
  • GENBANK/JQ060974
  • GENBANK/JQ060975
  • GENBANK/JQ060976
  • GENBANK/JQ060977
  • GENBANK/JQ060978
  • GENBANK/JQ060979
  • GENBANK/JQ060980
  • GENBANK/JQ060981
  • GENBANK/JQ060982
  • GENBANK/JQ060983
  • GENBANK/JQ060984
  • GENBANK/JQ060985
  • GENBANK/JQ060986
  • GENBANK/JQ060987
  • GENBANK/JQ060988
  • GENBANK/JQ060989
  • GENBANK/JQ060990
  • GENBANK/JQ060991
  • GENBANK/JQ060992
  • GENBANK/JQ060993
  • GENBANK/JQ060994
  • GENBANK/JQ060995
  • GENBANK/JQ060996