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Crystal structure of HLA B*18:01 in complex with QEIRTFSF, an 8-mer epitope from Influenza A
Structural highlights
FunctionPublication Abstract from PubMedOBJECTIVES: Seasonal influenza viruses cause roughly 650 000 deaths annually despite available vaccines. CD8(+) T cells typically recognise influenza-derived peptides from internal structural and non-structural influenza proteins and are an attractive avenue for future vaccine design as they could reduce the severity of disease following infection with diverse influenza strains. CD8(+) T cells recognise peptides presented by the highly polymorphic Human Leukocyte Antigens class I molecules (HLA-I). Each HLA-I variant has distinct peptide binding preferences, representing a significant obstacle for designing vaccines that elicit CD8(+) T cell responses across broad populations. Consequently, the rational design of a CD8(+) T cell-mediated vaccine would require the identification of highly immunogenic peptides restricted to a range of different HLA molecules. METHODS: Here, we assessed the immunogenicity of six recently published novel influenza-derived peptides identified by mass-spectrometry and predicted to bind to the prevalent HLA-B*18:01 molecule. RESULTS: Using CD8(+) T cell activation assays and protein biochemistry, we showed that 3/6 of the novel peptides were immunogenic in several HLA-B*18:01(+) individuals and confirmed their HLA-B*18:01 restriction. We subsequently compared CD8(+) T cell responses towards the previously identified highly immunogenic HLA-B*18:01-restricted NP(219) peptide. Using X-ray crystallography, we solved the first crystal structures of HLA-B*18:01 presenting immunogenic influenza-derived peptides. Finally, we dissected the first TCR repertoires specific for HLA-B*18:01 restricted pathogen-derived peptides, identifying private and restricted repertoires against each of the four peptides. CONCLUSION: Overall the characterisation of these novel immunogenic peptides provides additional HLA-B*18:01-restricted vaccine targets derived from the Matrix protein 1 and potentially the non-structural protein and the RNA polymerase catalytic subunit of influenza viruses. Characterisation of novel influenza-derived HLA-B*18:01-restricted epitopes.,Leong SL, Murdolo L, Maddumage JC, Koutsakos M, Kedzierska K, Purcell AW, Gras S, Grant EJ Clin Transl Immunology. 2024 May 10;13(5):e1509. doi: 10.1002/cti2.1509. , eCollection 2024. PMID:38737448[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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