T-cell development and function are regulated by MHC-associated self peptides, collectively referred to as the immunopeptidome. Large-scale mass spectrometry studies have highlighted three key features of the immunopeptidome. First, it is not a mirror of the proteome or the transcriptome, and its content cannot be predicted with currently available bioinformatic tools. Second, the immunopeptidome is more plastic than previously anticipated, and is molded by several cell-intrinsic and cell-extrinsic factors. Finally, the complexity of the immunopeptidome goes beyond the 20-amino acids alphabet encoded in the germline, and is not restricted to canonical reading frames. The large amounts of ‘dark matter’ in the immunopeptidome, such as polymorphic, cryptic and mutant peptides, can now be explored using novel proteogenomic approaches that combine mass spectrometry and next-generation sequencing.
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