Perturbations in epitope-specific T cells and their receptors following influenza and SARS-CoV-2 infection and vaccination

CD8+ T cells mount key anti-viral immune responses via recognition of conserved viral peptides presented by HLA. Identification and ex vivo analysis of immunogenic T cell epitopes is needed to understand the important role these cells play in susceptibility to severe disease and protection against future infections, particularly in high-risk populations. We analysed epitope-specific T cells in healthy and high-risk cohorts following influenza or SARS-CoV-2 infection or vaccination, including healthy adults, children, immunocompromised patients, Australian First Nations peoples and previously healthy adults with Long COVID.
We used immunopeptidomics to define influenza-derived peptides naturally processed and presented by prominent HLA alleles in First Nation Australians (HLA-A*11:01, 24:02, 34:01 and HLA-B*13:01). We probed memory CD8+ T-cells in First Nations individuals, identifying between six and eleven immunogenic influenza epitopes per allotype. This provides >95% population coverage for prominent CD8+ T-cell responses in Australian First Nations peoples.
We also analysed epitope-specific T cells directly ex vivo using panels of HLA class
I and class II tetramers presenting influenza or SARS-CoV-2 epitopes. Epitope-specific T cells were examined for their magnitude, activation, memory and exhaustion phenotype,
and T cell receptor (TCR) repertoire. We identified robust SARS-CoV-2 tetramer-specific
memory CD8+ and CD4+ T cells in unvaccinated adults and children following their first
SARS-CoV-2 infection. Following COVID vaccination, healthy and high-risk populations were found to have robust SARS-CoV-2 epitope-specific T cell populations and shared TCR motifs. Tetramer-specific T cell responses were comparable in recovered and Long COVID patients, with vaccination altering the immunodominance hierarchy of SARS-CoV-2 epitopes.
Our T cell studies examined unmanipulated influenza and SARS-CoV-2-specific T cells to understand primary and recall responses. These studies provide important insights into CD8+ and CD4+ T cell responses in acute respiratory virus patients across risk groups.