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

<div><p>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 <i>ex vivo</i> 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 <i>HLA-A*02</i> allele, <i>HLA-E *01</i>:<i>01/*01</i>:<i>03</i> 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^highRO^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 life-long 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.</p>