Abstract
Control of human cytomegalovirus (HCMV) depends on CD8+ T cell responses that are shaped by an individual's repertoire of MHC molecules. MHC class I presentation is modulated by a set of HCMV-encoded proteins. Here we show that HCMV immunoevasins differentially impair T cell recognition of epitopes from the same viral antigen, immediate-early 1 (IE-1), that are presented by different MHC class I allotypes. In the presence of immunoevasins, HLA-A- and HLA-B-restricted T cell clones were ineffective, but HLA-C*0702-restricted T cell clones recognized and killed infected cells. Resistance of HLA-C*0702 to viral immunoevasins US2 and US11 was mediated by the alpha3 domain and C-terminal region of the HLA heavy chain. In healthy donors, HLA-C*0702-restricted T cells dominated the T cell response to IE-1. The same HLA-C allotype specifically protected infected cells from attack by NK cells that expressed a corresponding HLA-C-specific KIR. Thus, allotype-specific viral immunoevasion allows HCMV to escape control by NK cells and HLA-A- and HLA-B-restricted T cells, while the virus becomes selectively vulnerable to an immunodominant population of HLA-C-restricted T cells. Our work identifies a T cell population that may be of particular efficiency in HCMV-specific immunotherapy.
Publication types
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Clinical Trial
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Research Support, Non-U.S. Gov't
MeSH terms
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Antigen Presentation*
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / pathology
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Cytomegalovirus / immunology*
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Cytomegalovirus Infections / immunology*
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Cytomegalovirus Infections / pathology
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Epitopes, T-Lymphocyte / immunology*
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Female
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Histocompatibility Antigens Class I / immunology*
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Humans
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Immediate-Early Proteins / immunology
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Immune Evasion*
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Killer Cells, Natural / immunology
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Killer Cells, Natural / pathology
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Male
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Protein Structure, Tertiary
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RNA-Binding Proteins / immunology
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Viral Envelope Proteins / immunology
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Viral Proteins / immunology
Substances
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Epitopes, T-Lymphocyte
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Histocompatibility Antigens Class I
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IE1 protein, cytomegalovirus
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Immediate-Early Proteins
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RNA-Binding Proteins
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US11 protein, herpesvirus
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US2 protein, Varicellovirus
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Viral Envelope Proteins
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Viral Proteins
Grants and funding
This work was supported by Deutsche Forschungsgemeinschaft (SFB-Transregio 36, SFB 490, and Clinical Research Group 183;
www.dfg.de), the Helmholtz Alliance for Immunotherapy of Cancer funded by the Initiative and Networking Fund of the Helmholtz Association (
www.dkfz.de/en/allianz-immuntherapie), and Deutsche José Carreras Leukämie Stiftung (
http://www.carreras-stiftung.de). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.