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

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

Author information

1
Centre de Recherche en Transplantation et Immunologie (CRTI), UMR1064, INSERM, Université de Nantes, Nantes, France.
2
Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.
3
CRCINA, UMR1232, INSERM, Université d'Angers, Université de Nantes, Nantes, France.
4
LabEx Immunology-Graft-Oncology (IGO), Nantes, France.
5
Laboratoire de Virologie, CHU Nantes, Nantes, France.
6
Etablissement Français du Sang (EFS), Région des Pays de la Loire, Nantes, France.
7
Institut Hospitalo-Universitaire European Center for Science in Transplantation and Immunology, Nantes, France.

Abstract

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.

PMID:
29709038
PMCID:
PMC5945056
DOI:
10.1371/journal.ppat.1007041
[Indexed for MEDLINE]
Free PMC Article

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