HLA-E-restricted Hantaan virus-specific CD8+ T cell responses enhance the control of infection in hemorrhagic fever with renal syndrome

Abstract

Infection with the Hantaan virus (HTNV) may result in severe hemorrhagic fever with renal syndrome (HFRS). The functions of HLA-E-restricted CD8⁺ T lymphocytes in virus control and vaccine development have recently received increased attention. The purpose of this research is to discover HLA-E-restricted CD8⁺ T cell epitopes on HTNV as well as the features of these epitope-specific CD8⁺ T cells in HFRS patients. To anticipate HLA-E-restricted HTNV epitopes, the NetMHCpan servers were utilized. The K562/HLA-E cell binding test and the enzyme-linked immunospot assay were used to confirm epitope binding to HLA-E. The number and features of HLA-E-restricted epitope-specific CD8⁺ T lymphocytes in HFRS patients were investigated using tetramer staining, intracellular cytokine labeling, proliferation, and cytotoxicity assays. Six HTNV-derived HLA-E-restricted CD8⁺ T cell epitopes were found in this study. In mild/moderate HFRS patients, the frequency of HLA-E-restricted epitope-specific CD8⁺ T cells was greater than in severe/critical patients. CD38⁺HLA-DR⁺ HLA-E-restricted CD8⁺ T cells were identified. Meanwhile, CD45RA⁺CCR7⁻ effector memory-re-expressing CD45RA T cells with early and intermediate maturation and differentiation characteristics predominated. Notably, CD8⁺ T cells from milder HFRS patients produced more interferon-γ, interleukin-2, and granzyme B, had a stronger proliferative potential, and were inversely linked with the amount of plasma HTNV virus load. Furthermore, HLA-E-restricted epitope-specific CD8⁺ T cells demonstrated improved cytotoxic activity in vitro during the acute stage of HFRS. Taken together, the findings demonstrate the protective effects of HLA-E-restricted CD8⁺ T cells during HTNV infection, suggesting that HLA-E-targeted vaccines against HTNV might be developed for HLA-diverse populations.