The impact of HLA class I and EBV latency-II antigen-specific CD8+ T cells on the pathogenesis of EBV+ Hodgkin lymphoma

In 40% of cases of classical Hodgkin Lymphoma (cHL), EBV-latency-II antigens (EBNA1/LMP1/LMP2A) are present (EBV+cHL) in the malignant cells and antigen presentation is intact. Previous studies have consistently shown that HLA-A*02 is protective in EBV+cHL, yet its role in disease pathogenesis is unknown. To explore the basis for this observation, gene expression was assessed in 33 cHL nodes. Interestingly, CD8 and LMP2A expression were strongly correlated and, for a given LMP2A level, CD8 was markedly elevated in HLA-A*02-ve versus HLA-A*02+ EBV+cHL patients, suggesting that LMP2A-specific CD8+ T-cell anti-tumoral immunity may be relatively ineffective in HLA-A*02-ve EBV+cHL. To ascertain the impact of HLA-class I on EBV-latency antigen-specific immuno-dominance, we used a step-wise functional T-cell approach. In newly diagnosed EBV+cHL, the magnitude of ex vivo LMP1/2A-specific CD8+ T-cell responses was elevated in HLA-A*02+ patients. Furthermore, in a controlled in vitro assay, LMP2A-specific CD8+ T-cells from healthy HLA-A*02 heterozygotes expanded to a greater extent with HLA-A*02-restricted compared to non-HLA-A*02-restricted cell lines. In an extensive analysis of HLA-class I-restricted immunity, immuno-dominant EBNA3A/3B/3C-specific CD8+ T-cell responses were stimulated by numerous HLA-class I molecules, whereas the sub-dominant LMP1/2A-specific responses were largely confined to HLA-A*02. Our results demonstrate that HLA-A*02 mediates a modest, but nonetheless stronger, EBV-specific CD8+ T-cell response than non-HLA-A*02 alleles, an effect confined to EBV-latency-II antigens. Thus, the protective effect of HLA-A*02 against EBV+cHL is not a surrogate association, but reflects the impact of HLA-class I on EBV-latency-II antigen-specific CD8+ T-cell hierarchies. This article is protected by copyright. All rights reserved.