CD8 T-cell responses towards conserved influenza B virus epitopes across anatomical sites and age.

Influenza B viruses (IBVs) cause substantive morbidity and mortality, and yet immunity towards IBVs remains understudied. CD8 T-cells provide broadly cross-reactive immunity and alleviate disease severity by recognizing conserved epitopes. Despite the IBV burden, only 18 IBV-specific T-cell epitopes restricted by 5 HLAs have been identified currently. A broader array of conserved IBV T-cell epitopes is needed to develop effective cross-reactive T-cell based IBV vaccines. Here we identify 9 highly conserved IBV CD8 T-cell epitopes restricted to HLA-B07:02, HLA-B08:01 and HLA-B35:01. Memory IBV-specific tetramerCD8 T-cells are present within blood and tissues. Frequencies of IBV-specific CD8 T-cells decline with age, but maintain a central memory phenotype. HLA-B07:02 and HLA-B08:01-restricted NP epitope-specific T-cells have distinct T-cell receptor repertoires. We provide structural basis for the IBV HLA-B07:02-restricted NS1 (11-mer) and HLA-B*07:02-restricted NP epitope presentation. Our study increases the number of IBV CD8 T-cell epitopes, and defines IBV-specific CD8 T-cells at cellular and molecular levels, across tissues and age.