The loss of immunodominant epitopes affects interferon-γ production and lytic activity of the human influenza virus-specific cytotoxic T lymphocyte responsein vitro

Abstract

SummaryIn the present study, we examined the effect of the loss of the human leucocyte antigen (HLA)-B*3501-restricted nucleoprotein (NP)418-426 epitope on interferon (IFN)-g-production and lytic activity of the human cytotoxic T lymphocyte (CTL) response in vitro. Extensive amino acid variation at T cell receptor contact residues of the NP418-426 epitope has led to repeated evasion from specific CTL. We generated recombinant influenza viruses with variants of the NP418-426 epitope, which were used to stimulate peripheral blood mononuclear cells obtained from six HLA-B*3501-positive study subjects in order to expand virus-specific CTL. Loss of the NP418-426 epitope resulted in a significant reduction of IFN-g-expressing CD8+ T cells, similar to that observed previously after the loss of the HLA-B*2705-restricted NP383-391 epitope. In addition, the effect of the loss of the NP418-426 epitope on the lytic activity of the virus-specific CTL response was assessed. Also this functional property of the virus-specific CTL response was affected significantly by the loss of this and the NP383-391 epitope, as determined using the newly developed fluorescent antigen-transfected target cell (FATT)-CTL assay. These findings indicate that the loss of single immunodominant epitopes affects the functionality of the virus-specific CTL response significantly.

Cross-reactive CD8 + T-cell immunity between the pandemic H1N1-2009 and H1N1-1918 influenza A viruses

“…Sequence analysis of influenza viruses established that many of the A (H1N1)-2009-derived variable peptides within the main T-cell immunogenic proteins (6,11), nucleoprotein (NP) and matrix-1 (M1), are more like the pandemic 1918-H1N1 strain rather than the seasonal influenza strains (Table S1). Based on these results, we focused on the variable (although highly cross-reactive between different variants derived from seasonal influenza viruses) immunodominant NP [418][419][420][421][422][423][424][425][426] peptide that binds a large B7 allelic family (12,13) found throughout human populations (HLA-B*3501/ HLA-B*3503/HLA-B*0702) and probed memory CD8 + T-cell specificity for 12 different NP 418 mutants derived from a spectrum of seasonal and pandemic viruses (8,(12)(13)(14). These include the A(H1N1)-2009 virus, the 1918-H1N1 virus, and 10 seasonal viruses from 1933 to 2005 (Table 1).…”

NS-based live attenuated H1N1 pandemic vaccines protect mice and ferrets

“…A drawback of using the 6 internal-protein encoding vRNAs of ca A/AA/6/60 is that the cytotoxic T lymphocyte epitopes present in influenza A virus have mutated because of host immune pressure, which reduces immune recognition of the internal proteins expressed by currently circulating strains [45][46][47][48]. Additionally, many immune evading amino acid substitutions are present when novel reassortants like the H1N1pdm virus emerge from animal reservoirs.…”

Immunity to seasonal and pandemic influenza A viruses

“…Although mutations that disrupt pMHC-I binding provide an effective escape from CD8 + T cell immunity, mutations at TCR contact sites are more common [92, 95]. The NP418-426 peptide consistently and at high levels presented by the HLA-B7 superfamily (including HLA-B*3501, B*3503, B*0702) has sequentially mutated at 4 different TCR contact positions, generating over 20 different peptide sequences over the past 90 years [84, 96, 97].…”