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Principal Investigator: MALINI RAGHAVAN
Organization: UNIVERSITY OF MICHIGAN AT ANN ARBOR
Fiscal Year: 2023
Award: $227,280
Funding agency: National Institute of Allergy and Infectious Diseases
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.
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Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 vaccine><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome coronavirus 2 vaccination><Severe acute respiratory syndrome coronavirus 2 vaccine><Severe acute respiratory syndrome related corona virus 2><Specificity><Staining method><Stains><Structure><T cell 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