Optimal positive selection of CD8+ T cells requires the expression of β5t-containing thymoproteosome (tCP) in cortical thymic epithelial cells. In Nature Communications, Murata and colleagues show that the thymoproteasome produces unique cleavage motifs in the digested peptides, which leads to a major histocompatibility complex (MHC) class I–associated peptide repertoire with enrichment for low-affinity TCR ligands. Using mass spectrometry to sequence the peptides generated in vitro by isolated tCPs and the MHC class I–binding peptides in tCP-expressing mouse embryonic fibroblasts, the authors show that tCPs generate an MHC class I–binding peptide repertoire distinct from the immunoproteasomes. Although high-affinity peptides are also produced, the tCP-generated repertoire shows enrichment for peptides with low affinity for a wide range of TCRs, which, in fetal thymic organ culture, favors the positive selection of CD8+ single-positive thymocytes. In contrast, immunoproteasomes produce peptide with highly diverse TCR affinities.
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Visan, I. Thymoproteasome bias. Nat Immunol 16, 801 (2015). https://doi.org/10.1038/ni.3243
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DOI: https://doi.org/10.1038/ni.3243