HLA-E-Restricted Immune Responses Are Crucial for the Control of EBV Infections and the Prevention of PTLD.

Primary Epstein-Barr virus (EBV) infections may cause infectious mononucleosis (IM), while EBV-reactivations in solid-organ (SOT) and hematopoietic stem cell transplant (HSCT) recipients are associated with post-transplantation lymphoproliferative disorders (PTLD). It is still unclear, why only a minority of primary EBV-infected individuals develop IM, and why only some patients progress to EBV+PTLD post-transplantation. We now investigated, whether non-classical HLA-E-restricted immune responses have a significant impact on the development of EBV-diseases in the individual host. Based on a large study cohort of 1404 patients and controls as well as on functional natural killer (NK) and CD8+ T cell analyses, we could demonstrate that the highly expressed HLA-E*0103/0103 genotype is protective against IM, due to the induction of potent EBV BZLF1-specific HLA-E-restricted CD8+ T cell responses, which efficiently prevent the in vitro viral dissemination. Furthermore, we provide evidence that the risk of symptomatic EBV-reactivations in immunocompetent individuals as well as in immunocompromised transplant recipients depends on variations in the inhibitory NKG2A/LMP-1/HLA-E axis. We show that EBV-strains encoding for the specific LMP-1 peptide variants GDPHLPTL or GGDPPLPTL, presented by HLA-E, elicit strong inhibitory NKG2A+ NK and CD8+ T cell responses. The presence of EBV-strains encoding for both peptides was highly associated with symptomatic EBV-reactivations. The further progression to EBV+PTLD was highly associated with the presence of both peptide-encoding EBV-strains and the expression of HLA-E*0103/0103 in the host. Thus, HLA-E-restricted immune responses and the NKG2A/LMP-1/HLA-E axis are novel predictive markers for EBV+PTLD in transplant recipients and should be considered for future EBV vaccine design.