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

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

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.

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