HLA class I peptidome diversities and CD8+ T cell responses to COVID-19 vaccines

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CD8+ T cells recognize short peptide antigens in the context of major histocompatibility complex class I (MHC- I) proteins. Three sets of genes, the human leukocyte antigens (HLA) HLA-A, HLA-B and HLA-C encode the heavy chains of human MHC-I (HLA-I) proteins, which also contain a light chain (β2-microglobulin) and a peptide. The HLA-A, HLA-B and HLA-C genes are highly polymorphic. In cells, individual HLA-I allotypes can bind to many peptides derived from intracellular proteins. Cell infection induces the binding of specific pathogen-derived peptides, which can trigger CD8+ T cell recognition and immunity. Recent mass spectrometric (MS) studies have identified the sequences of thousands of peptides that bind to HLA-I allotypes, the individual peptidomes. Inspections of these peptide sequences lead to the hypothesis of variable peptide repertoire sizes among HLA-I allotypes and resulting variations in the breadth of CD8+ T cell responses to SARS-Cov2 infection and COVID-19 vaccination. To address this hypothesis, in the proposed studies, quantitative high resolution mass spectrometry (MS) will be used to measure differences in self-peptide repertoire sizes for selected HLA-B allotypes. Factors that underlie variations in repertoire sizes will be examined. Additionally, the breadth of SARS-CoV-2 Spike epitopes that induce CD8+ T cell activation will be measured using blood from select HLA genotyped blood donors who have been vaccinated against COVID-19, examining the prevalence of epitope breadth variations among HLA-I allotypes. Taken together, these studies address the prevalence and consequences of variable HLA-I peptidome diversities, with a focus on immunity induced by COVID-19 vaccines. The knowledge resulting from these studies will inform on key aspects of HLA- I biology and vaccine-indued immunity.