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.
Susan L Heatley  1 ,  Gabriella Pietra  2 ,  Jie Lin  1 ,  Jacqueline M L Widjaja  1 ,  Christopher M Harpur  1 ,  Sue Lester  3 ,  Jamie Rossjohn  4 ,  Jeff Szer  5 ,  Anthony Schwarer  6 ,  Kenneth Bradstock  7 ,  Peter G Bardy  8 ,  Maria Cristina Mingari  9 ,  Lorenzo Moretta  10 ,  Lucy C Sullivan  1 ,  Andrew G Brooks  11
Affiliations
  • 1. Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia.
  • 2. Department of Experimental Medicine, University of Genova, Genova 16132, Italy.
  • 3. Department of Rheumatology, The Queen Elizabeth Hospital, South Australia 5011, Australia.
  • 4. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia.
  • 5. Department of Clinical Haematology and Bone Marrow Transplant Service, Royal Melbourne Hospital, Victoria 3050, Australia.
  • 6. Malignant Haematology and Stem Cell Transplantation Service, The Alfred Hospital, Victoria 3004, Australia.
  • 7. Department of Haematology, Westmead Hospital, New South Wales 2145, Australia.
  • 8. Director of Cancer Services, Royal Adelaide Hospital, South Australia 5000, Australia.
  • 9. Department of Experimental Medicine, University of Genova, Genova 16132, Italy; IRCCS AOU San Martino-IST, Genova 16132, Italy.
  • 10. Istituto Giannina Gaslini, Genova 16147, Italy.
  • 11. Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia. Electronic address: [email protected].
PMID: 23335510 DOI: 10.1074/jbc.M112.409672
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.