title: HLA-E-restricted recognition of human cytomegalovirus by a subset of cytolytic T lymphocytes.
abstract: Natural killer (NK)-cytotoxic T lymphocytes (CTL) are a subset of CD8(+) cytolytic T lymphocytes that express human leukocyte antigen (HLA) class I-specific inhibitory receptors. They are detectable as monoclonal expansions in the blood of cytomegalovirus (CMV)-seropositive individuals displaying particular HLA-Cw allotypes. Similar to NK cells, they are capable of killing various allogeneic tumor cell lines, a function referred to as "NK-like activity." The mechanism underlying this unusual functional property has recently been clarified. Via their T-cell receptor, NK-CTL recognize the nonclassical HLA class I molecule HLA-E, which is characterized by a limited polymorphism and by the ability to bind peptides derived from the leader sequence of various HLA class I alleles as well as from few viral proteins. The analysis of the T-cell receptor avidity revealed that NK-CTL recognize with high avidity a CMV UL40-derived peptide. The HLA-E-restricted recognition of CMV by NK-CTL may represent an important immunologic strategy in defenses against this virus. Indeed, unlike conventional CTL, NK-CTL mediated lysis is apparently not affected by the downregulation of major histocompatibility complex class I that occurs during CMV infection. Because the CMV UL40-derived peptide is identical to the one generated from the leader sequence of various HLA-Cw alleles, NK-CTL are also able to display an "HLA-E-dependent alloreactivity" against allogeneic target cells expressing appropriate HLA-Cw alleles. This broad ability to recognize and kill allogeneic cells may pose serious problems in transplantation.
authors.affiliation: Dipartimento di Medicinia Sperimentale, Centro di Eccellenza per Ricerche Biomediche , Università degli Studi di Genova, Genova, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Romagnani
authors.forename: Gabriella
authors.initials: G
authors.lastname: Pietra
authors.forename: Michela
authors.initials: M
authors.lastname: Falco
authors.forename: Paola
authors.initials: P
authors.lastname: Mazzarino
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Moretta
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Mingari
mesh_terms: D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D002460:Cell Line; D003587:Cytomegalovirus / Q000276:immunology*; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000276:immunology; D005434:Flow Cytometry; D006680:HLA Antigens / Q000235:genetics / Q000276:immunology*; D015236:HLA-C Antigens / Q000276:immunology; D004854:Herpesvirus 4, Human / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology; D001613:beta 2-Microglobulin / Q000235:genetics / Q000276:immunology; D000097625:HLA-E Antigens
chemical_list: D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D000911:Antibodies, Monoclonal; D006680:HLA Antigens; D015236:HLA-C Antigens; D015395:Histocompatibility Antigens Class I; D007371:Interferon-gamma; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D014764:Viral Proteins; D001613:beta 2-Microglobulin; D000097625:HLA-E Antigens; C489516:Tap2 protein, mouse; C404228:UL40 glycoprotein, Cytomegalovirus