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

Journal: The Journal of biological chemistry 2013;288(12):8679-8690

PMID: 23335510

Free Full Text on Elsevier Science View on PubMed

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.

Address: Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia.; Department of Experimental Medicine, University of Genova, Genova 16132, Italy.; Department of Rheumatology, The Queen Elizabeth Hospital, South Australia 5011, Australia.; Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia.; Department of Clinical Haematology and Bone Marrow Transplant Service, Royal Melbourne Hospital, Victoria 3050, Australia.; Malignant Haematology and Stem Cell Transplantation Service, The Alfred Hospital, Victoria 3004, Australia.; Department of Haematology, Westmead Hospital, New South Wales 2145, Australia.; Director of Cancer Services, Royal Adelaide Hospital, South Australia 5000, Australia.; Department of Experimental Medicine, University of Genova, Genova 16132, Italy; IRCCS AOU San Martino-IST, Genova 16132, Italy.; Istituto Giannina Gaslini, Genova 16147, Italy.; Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia. Electronic address: [email protected].

DOI: 10.1074/jbc.M112.409672

Link outs

Free resources

Full Text Sources:

Other Literature Sources:

Molecular Biology Databases:

Research Materials:

https://antibodies.cancer.gov/detail/CPTC-HLA-DQA1...

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