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It has widely been accepted that major histocompatibility complex class I molecules (MHC-I) are limited to binding small peptides of 8–10 residues in length. However, this consensus has recently been challenged with the identification of longer peptides (≥11 residues) that can also elicit cytotoxic CD8 +  T cell responses. Indeed, a growing number of studies demonstrate that these non-canonical epitopes are important targets for the immune system. As long epitopes represent up to 10% of the peptide repertoire bound to MHC-I molecules, here we review their impact on antigen presentation by MHC-I, TCR recognition, and T cell immunity.

Molecular challenges imposed by MHC-I restricted long epitopes on T cell immunity