HCMV triggers frequent and persistent UL40-specific unconventional HLA-E-restricted CD8 T-cell responses with potential autologous and allogeneic peptide recognition

PLoS Pathog. 2018 Apr 30;14(4):e1007041. doi: 10.1371/journal.ppat.1007041. eCollection 2018 Apr.


Immune response against human cytomegalovirus (HCMV) includes a set of persistent cytotoxic NK and CD8 T cells devoted to eliminate infected cells and to prevent reactivation. CD8 T cells against HCMV antigens (pp65, IE1) presented by HLA class-I molecules are well characterized and they associate with efficient virus control. HLA-E-restricted CD8 T cells targeting HCMV UL40 signal peptides (HLA-EUL40) have recently emerged as a non-conventional T-cell response also observed in some hosts. The occurrence, specificity and features of HLA-EUL40 CD8 T-cell responses remain mostly unknown. Here, we detected and quantified these responses in blood samples from healthy blood donors (n = 25) and kidney transplant recipients (n = 121) and we investigated the biological determinants involved in their occurrence. Longitudinal and phenotype ex vivo analyses were performed in comparison to HLA-A*02/pp65-specific CD8 T cells. Using a set of 11 HLA-E/UL40 peptide tetramers we demonstrated the presence of HLA-EUL40 CD8 αβT cells in up to 32% of seropositive HCMV+ hosts that may represent up to 38% of total circulating CD8 T-cells at a time point suggesting a strong expansion post-infection. Host's HLA-A*02 allele, HLA-E *01:01/*01:03 genotype and sequence of the UL40 peptide from the infecting strain are major factors affecting the incidence of HLA-EUL40 CD8 T cells. These cells are effector memory CD8 (CD45RAhighROlow, CCR7-, CD27-, CD28-) characterized by a low level of PD-1 expression. HLA-EUL40 responses appear early post-infection and display a broad, unbiased, Vβ repertoire. Although induced in HCMV strain-dependent, UL4015-23-specific manner, HLA-EUL40 CD8 T cells are reactive toward a broader set of nonapeptides varying in 1-3 residues including most HLA-I signal peptides. Thus, HCMV induces strong and life-long lasting HLA-EUL40 CD8 T cells with potential allogeneic or/and autologous reactivity that take place selectively in at least a third of infections according to virus strain and host HLA concordance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antigen Presentation
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / virology
  • Case-Control Studies
  • Cells, Cultured
  • Cytomegalovirus / drug effects
  • Cytomegalovirus / immunology*
  • Cytomegalovirus Infections / drug therapy
  • Cytomegalovirus Infections / immunology*
  • Cytomegalovirus Infections / metabolism
  • Cytomegalovirus Infections / virology
  • Female
  • Histocompatibility Antigens Class I / immunology
  • Histocompatibility Antigens Class I / metabolism*
  • Humans
  • Kidney Transplantation*
  • Male
  • Middle Aged
  • Peptide Fragments / pharmacology*
  • Retrospective Studies
  • T-Lymphocytes, Cytotoxic / drug effects
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Cytotoxic / metabolism
  • T-Lymphocytes, Cytotoxic / virology
  • Transplantation, Autologous
  • Viral Proteins / metabolism*


  • HLA-E antigen
  • Histocompatibility Antigens Class I
  • Peptide Fragments
  • UL40 glycoprotein, Cytomegalovirus
  • Viral Proteins

Grant support

This study was funded by: Thesis fellowship from the Ministère de l'enseignement supérieur, de la Recherche et de l'Innovation to NJ (http://www.enseignementsup-recherche.gouv.fr/); Agence Nationale de la Recherche (http://www.agence-nationale-recherche.fr/) to NG and BC (Award number: ANR-11-LABX-016-01) and BC (Award number: ANR-RC12-0465-16); Agence de la Biomédecine (https://www.agence-biomedecine.fr/) to BC (Appel d'offre Recherche et Greffe 2013); and Région Pays de la Loire (http://www.paysdelaloire.fr/) to BC (Award name: Pari Scientifique HYPROTEC RN14044). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.