title: Polymorphism in human cytomegalovirus UL40 impacts on recognition of human leukocyte antigen-E (HLA-E) by natural killer cells.
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.
authors: Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia.
authors: Susan L
authors: SL
authors: Heatley
authors: Department of Experimental Medicine, University of Genova, Genova 16132, Italy.
authors: Gabriella
authors: G
authors: Pietra
authors: Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia.
authors: Jie
authors: J
authors: Lin
authors: Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia.
authors: Jacqueline M L
authors: JML
authors: Widjaja
authors: Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia.
authors: Christopher M
authors: CM
authors: Harpur
authors: Department of Rheumatology, The Queen Elizabeth Hospital, South Australia 5011, Australia.
authors: Sue
authors: S
authors: Lester
authors: Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia.
authors: Jamie
authors: J
authors: Rossjohn
authors: Department of Clinical Haematology and Bone Marrow Transplant Service, Royal Melbourne Hospital, Victoria 3050, Australia.
authors: Jeff
authors: J
authors: Szer
authors: Malignant Haematology and Stem Cell Transplantation Service, The Alfred Hospital, Victoria 3004, Australia.
authors: Anthony
authors: A
authors: Schwarer
authors: Department of Haematology, Westmead Hospital, New South Wales 2145, Australia.
authors: Kenneth
authors: K
authors: Bradstock
authors: Director of Cancer Services, Royal Adelaide Hospital, South Australia 5000, Australia.
authors: Peter G
authors: PG
authors: Bardy
authors: Department of Experimental Medicine, University of Genova, Genova 16132, Italy; IRCCS AOU San Martino-IST, Genova 16132, Italy.
authors: Maria Cristina
authors: MC
authors: Mingari
authors: Istituto Giannina Gaslini, Genova 16147, Italy.
authors: Lorenzo
authors: L
authors: Moretta
authors: Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia.
authors: Lucy C
authors: LC
authors: Sullivan
authors: Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia. Electronic address: agbrooks@unimelb.edu.au.
authors: Andrew G
authors: AG
authors: Brooks
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001665:Binding Sites; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000235:genetics* / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000628:therapy; D008228:Lymphoma, Non-Hodgkin / Q000628:therapy; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000378:metabolism; D051920:NK Cell Lectin-Like Receptor Subfamily D / Q000378:metabolism; D010802:Phylogeny; D011110:Polymorphism, Genetic; D011485:Protein Binding; D017422:Sequence Analysis, DNA; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D055815:Young Adult; D000097625:HLA-E Antigens
chemical_list: D015395:Histocompatibility Antigens Class I; D055654:NK Cell Lectin-Like Receptor Subfamily C; D051920:NK Cell Lectin-Like Receptor Subfamily D; D014764:Viral Proteins; D000097625:HLA-E Antigens; C497869:KLRD1 protein, human; C404228:UL40 glycoprotein, Cytomegalovirus