Clinical & translational immunology · 2026
Assessing CD8+ T cell cross-reactivity to influenza A, B and C virus-derived peptides presented by HLA-B*18:01.
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Murdolo Lawton D, Leong Samuel Liwei, Maddumage Janesha C, D'Orsogna Lloyd, Chatzileontiadou Demetra Sm, Grant Emma J, Gras Stephanie
Аннотация
OBJECTIVES: Despite the availability of vaccines, influenza viruses still cause substantial morbidity and mortality. This highlights the need for improved vaccines and novel therapeutics. CD8+ T cells recognise conserved viral epitopes and can provide broad protection, making them attractive targets for next-generation vaccine design. A key step in this process is to identify T cell epitopes across influenza viruses. Here, we characterised three homologous influenza Polymerase Basic 1 (PB1)-derived peptides from influenza viruses (PB1-A310, PB1-B310 and PB1-C312, respectively) presented by the common, but understudied, HLA-B*18:01 molecule.
METHODS: We used a thermal melt assay and X-ray crystallography to assess the stability and structural features of each peptide. CD8+ T-cell responses were evaluated using intracellular cytokine staining with HLA-B*18:01+ samples.
RESULTS: The structures of HLA-B*18:01 presenting each peptide were solved, including the first structure of HLA-B*18:01 presenting a Gammainfluenzavirus (formerly influenza C virus) derived peptide. PB1-C312 exhibited a higher thermal stability and a different conformation compared to PB1-A310 and PB1-B310. CD8+ T cell responses varied among samples, with PB1-A310 eliciting the strongest activation. Minimal T cell cross-reactivity was observed and was mostly between PB1-A310 and PB1-B310 likely reflecting shared structural features.
CONCLUSION: These findings further expand knowledge on peptide presentation by the common HLA-B*18:01 molecule, and the limitations on CD8+ T cell cross-recognition of this PB1-derived epitope across influenza lineages. This highlights the importance of more research on cross-lineage T cell cross-reactivity that could inform the design of broadly protective T cell-based vaccines and therapeutics.
METHODS: We used a thermal melt assay and X-ray crystallography to assess the stability and structural features of each peptide. CD8+ T-cell responses were evaluated using intracellular cytokine staining with HLA-B*18:01+ samples.
RESULTS: The structures of HLA-B*18:01 presenting each peptide were solved, including the first structure of HLA-B*18:01 presenting a Gammainfluenzavirus (formerly influenza C virus) derived peptide. PB1-C312 exhibited a higher thermal stability and a different conformation compared to PB1-A310 and PB1-B310. CD8+ T cell responses varied among samples, with PB1-A310 eliciting the strongest activation. Minimal T cell cross-reactivity was observed and was mostly between PB1-A310 and PB1-B310 likely reflecting shared structural features.
CONCLUSION: These findings further expand knowledge on peptide presentation by the common HLA-B*18:01 molecule, and the limitations on CD8+ T cell cross-recognition of this PB1-derived epitope across influenza lineages. This highlights the importance of more research on cross-lineage T cell cross-reactivity that could inform the design of broadly protective T cell-based vaccines and therapeutics.