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

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-E[UL40]) have recently emerged as a non-conventional T-cell response also observed in some hosts. The occurrence, specificity and features of HLA-E[UL40] 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-E[UL40] 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-E[UL40] CD8 T cells. These cells are effector memory CD8 (CD45RA[high]RO[low], CCR7-, CD27-, CD28-) characterized by a low level of PD-1 expression. HLA-E[UL40] responses appear early post-infection and display a broad, unbiased, Vβ repertoire. Although induced in HCMV strain-dependent, UL40[15-23]-specific manner, HLA-E[UL40] 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 lifelong lasting HLA-E[UL40] 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.
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PLoS Pathogens, Public Library of Science, 2018, 14 (4), pp.e1007041. 〈10.1371/journal.ppat.1007041〉
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Nicolas Jouand, Céline Bressollette-Bodin, Nathalie Gérard, Magali Giral, Pierrick Guérif, et al.. HCMV triggers frequent and persistent UL40- specific unconventional HLA-E-restricted CD8 T-cell responses with potential autologous and allogeneic peptide recognition. PLoS Pathogens, Public Library of Science, 2018, 14 (4), pp.e1007041. 〈10.1371/journal.ppat.1007041〉. 〈inserm-01812003〉

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