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Abstract
The magnitude of T cell responses to infection is a function of the naïve T cell repertoire combined with the context and duration of antigen presentation. Using mass spectrometry, we identify and quantify 21 class 1 MHC-restricted influenza A virus (IAV)-peptides following either direct or cross-presentation. All these peptides, including seven novel epitopes, elicit T cell responses in infected C57BL/6 mice. Directly presented IAV epitopes maintain their relative abundance across distinct cell types and reveal a broad range of epitope abundances. In contrast, cross-presented epitopes are more uniform in abundance. We observe a clear disparity in the abundance of the two key immunodominant IAV antigens, wherein direct infection drives optimal nucleoprotein (NP)366–374 presentation, while cross-presentation is optimal for acid polymerase (PA)224–233 presentation. The study demonstrates how assessment of epitope abundance in both modes of antigen presentation is necessary to fully understand the immunogenicity and response magnitude to T cell epitopes.
Highlights
The magnitude of T cell responses to infection is a function of the naïve T cell repertoire combined with the context and duration of antigen presentation
A number of CD8+ T-cell epitopes have been identified in the B6 model of influenza A virus (IAV) infection[7,8,9] (Table 1), their identification has been predominantly achieved through epitope prediction and screening of T-cell responses
The length of the newly identified peptides likely contributed to their obscurity to date since previous publication of a widely tested potential repertoire of IAV-derived epitopes generated via a matrix-based algorithm, assumed lengths of 8 aa for Kb binders and 9–10 aa for Db binders[9]
Summary
The magnitude of T cell responses to infection is a function of the naïve T cell repertoire combined with the context and duration of antigen presentation. We identify and quantify 21 class 1 MHC-restricted influenza A virus (IAV)-peptides following either direct or cross-presentation All these peptides, including seven novel epitopes, elicit T cell responses in infected C57BL/6 mice. Using an in vitro mass spectrometry-based strategy to identify and quantitate naturally processed H-2b-restricted peptides, we identify 21 IAV-derived peptides following both direct infection and cross-presentation These include seven novel peptides, presented by H-2Db and H-2Kb. All identified peptides are able to elicit CD8+ T-cell responses following infection, indicating that epitope presentation following in vitro infection is representative of that during in vivo infection. The addition of quantitative MS data from directly infected cells and crosspresented viral antigen is used along with other variables (naïve T-cell precursor frequency, MHCI-binding affinity, protein abundance) to model the drivers of T-cell response magnitude to IAV This analysis indicates significant contributions of both direct and cross-presentation, as well as peptide affinity for MHCI, in establishing the IAV-specific CD8+ T-cell immunodominance hierarchy
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