A targeted single mutation in influenza A virus universal epitope transforms immunogenicity and protective immunity via CD4 + T cell activation

摘要

CD4 + T cells are central to adaptive immunity. Their role in cross -protection in viral infections such as influenza and severe acute respiratory syndrome (SARS) is well documented; however, molecular rules governing T cell receptor (TCR) engagement of peptide -human leukocyte antigen (pHLA) class II are less understood. Here, we exploit an aspect of HLA class II presentation, the peptide -flanking residues (PFRs), to "tune"CD4 + T cell responses within an in vivo model system of influenza. Using a recombinant virus containing targeted substitutions at immunodominant HLA-DR1 epitopes, we demonstrate limited weight loss and improved clinical scores after heterosubtypic re -challenge. We observe enhanced protection linked to lung -derived influenza -specific CD4 + and CD8 + T cells prior to re -infection. Structural analysis of the ternary TCR:pHLA complex identifies that flanking amino acids influence side chains in the core 9-mer peptide, increasing TCR affinity. Augmentation of CD4 + T cell immunity is achievable with a single mutation, representing a strategy to enhance adaptive immunity that is decoupled from vaccine modality.