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), whereas EBV reactivations in solid organ and hematopoietic stem cell transplant recipients are associated with posttransplantation lymphoproliferative disorders (PTLDs). It is still unclear why only a minority of primary EBV-infected individuals develop IM, and why only some patients progress to EBV+PTLD after transplantation. We now investigated whether nonclassic human leukocyte antigen E (HLA-E)-restricted immune responses have a significant impact on the development of EBV diseases in the individual host. On the basis of 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 GGDPHLPTL 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.