In 2018 the World Health Organisation listed influenza A virus (IAV) pandemics as one of the top threats to global health. Influenza pandemics occur as a result of the emergence of antigenically distinct strains, which arise due to genomic re-assortment. The resulting strains have different antigenic make-ups and impact the ability of the immune system to respond quickly following infection.
Many mutations acquired by IAV occur in the surface glycoproteins haemagglutinin (HA) and neuraminidase (NA), making it difficult for the adaptive immune system to recognise distinct strains. The ability of CD4+ T-cells to respond to naturally occurring peptide variants derived from these proteins has not been investigated. Furthermore, differences in the response to IAV in individuals expressing common HLA class II allomorphs have been observed in clinical studies. However, the molecular mechanisms surrounding these associations in IAV has not yet been investigated.
As the current influenza vaccine triggers a haemagglutinin based response which has been shown to involve the activity of CD4+ T-cells, it is essential to gain an understanding of how CD4+ T-cells respond to different mutants. Moreover, as individuals expressing particular HLA class II allomorphs are at a higher risk of developing severe IAV infection, further investigation into the basis of these associations is warranted.
Through stimulating T-cells from donors expressing two common HLA class II allomorphs with peptide variants derived from pandemic and epidemic IAV strains, I have identified novel, naturally occurring CD4+ T-cell epitopes, determined the level of cross-reactivity, phenotype and polyfunctionality of the responding CD4+ T-cells and have shown that the response differs between donors expressing different HLA molecules. I have also used X-ray crystallography to solve the structure of HLA-DRB1*11:01 presenting different HA variants to gain insight into the molecular basis of the HA-directed CD4+ T-cell response.