HLA-E–restricted immune responses are crucial for the control of EBV infections and the prevention of PTLD

Abstract

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.

Matching or genetic engineering of HLA Class I and II facilitates successful allogeneic ‘off-the-shelf’ regulatory T cell therapy

“…HLA-E is a non-classical HLA class Ib molecule with only two alleles present in diverse populations (HLA-E*01:01 and HLA-E*01:03) (44). HLA-E primarily presents signal peptides from other HLA-I molecules; however, some reports also demonstrate that HLA-E*01:03 can present viral peptides from CMV or EBV (45,46). Binding of HLA-E to CD94/NKG2A or CD94/NKG2B on NK cells or CD8 T cells inhibits said cells, explaining the protective effect observed in vitro (47).…”

“…Binding of HLA-E to CD94/NKG2A or CD94/NKG2B on NK cells or CD8 T cells inhibits said cells, explaining the protective effect observed in vitro (47). In contrast, HLA-E can also present viral peptides to activate NK cells by binding the conserved NKG2C (48) or EBV-specific and HLA-E-restricted CD8 + T cells (46,49). Previous strategies to create hypoimmunogenic cells implemented HLA-E fusion proteins that lack antigen-presentation by covalently linking B2M, HLA-E and a non-polymorphic signal peptide of HLA-G into a single molecule (23,24).…”

Epstein–Barr virus‐associated lymphomas decoded

“…38,42 More recently, it has been shown that variations in CD94/NKG2A-HLA-E interactions on T-and NK-cell subsets have functional relevance in EBV control. 158…”

“…Mechanistic studies suggest that the association is due to the impact of HLA‐class I molecules on the magnitude of CD8+ T‐cell responses to latent EBV‐antigens and that polymorphisms in EBV‐latency genes influence the potency of CD8+ T‐cell responses in EBV‐associated PTLD 38,42 . More recently, it has been shown that variations in CD94/NKG2A–HLA‐E interactions on T‐ and NK‐cell subsets have functional relevance in EBV control 158 …”

Viral escape from NK‐cell‐mediated immunosurveillance: A lesson for cancer immunotherapy?

“…These NKG2A − NKG2C + NK-cell products combine the absence of inhibition through the lack of NKG2A with robust activation through the presence of NKG2C and thus represent optimal candidates for the treatment of tumors enriched for HLA-E expression. Of interest, a sensitizing effect of HLA-E in viral infections has also been demonstrated: Not all viral HLA-E-restricted peptides mediate immune evasion and peptides from human immunodeficiency virus (HIV)-1, Epstein-Barr virus (EBV), as well as SARS-CoV-2 have been shown to prevent the binding of NKG2A to HLA-E/viral peptide complexes, thereby rendering infected cells susceptible to NKG2A + NK-cell attack [33][34][35][36]. Along those lines, an intriguing future approach to fine-tune NK-cell responses could lie in specifically altering the tumor peptidome with the goal to reduce inhibition through NKG2A, similar to what has been suggested regarding the activation of unconventional T cells [37].…”