Presentation of an immunodominant immediate-early CD8+ T cell epitope resists human cytomegalovirus immunoevasion

PLoS Pathog. 2013;9(5):e1003383. doi: 10.1371/journal.ppat.1003383. Epub 2013 May 23.

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

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigen Presentation*
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / pathology
  • Cytomegalovirus / immunology*
  • Cytomegalovirus Infections / immunology*
  • Cytomegalovirus Infections / pathology
  • Epitopes, T-Lymphocyte / immunology*
  • Female
  • Histocompatibility Antigens Class I / immunology*
  • Humans
  • Immediate-Early Proteins / immunology
  • Immune Evasion*
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / pathology
  • Male
  • Protein Structure, Tertiary
  • RNA-Binding Proteins / immunology
  • Viral Envelope Proteins / immunology
  • Viral Proteins / immunology

Substances

  • Epitopes, T-Lymphocyte
  • Histocompatibility Antigens Class I
  • IE1 protein, cytomegalovirus
  • Immediate-Early Proteins
  • RNA-Binding Proteins
  • US11 protein, herpesvirus
  • US2 protein, Varicellovirus
  • Viral Envelope Proteins
  • Viral Proteins

Grant support

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.