The extent to which unconventional forms of antigen presentation drive T cell immunity is unknown. By convention, CD8 T cells recognize viral peptides in association with classical major histocompatibility complex (MHC) class I, or MHC-Ia, but immune surveillance can in some cases be directed against peptides presented by non-classical MHC-Ib, for example the MHC-E proteins (Qa-1 in mice and HLA-E in humans); however, the overall importance of non-classical responses in antiviral immunity remains unclear. Similarly uncertain is the importance of “cryptic” viral epitopes, defined as those undetectable by conventional mapping techniques. Here, we used an immunopeptidomics approach to search for unconventional epitopes that drive T cell responses in mice infected with influenza A virus (IAV). We identify a nine amino acid epitope, termed M-SL9, that drives a co-immunodominant, cytolytic CD8 T cell response that is unconventional in two ways: first, it is presented by Qa-1, and second, it maps to an alternative reading frame of the influenza matrix protein 1 (M1) mRNA and appears to derive mainly from an unannotated 16-residue peptide that is dispensable for viral replication. Presentation and immunogenicity of M-SL9 were dependent on the second AUG codon of the positive sense matrix RNA segment, supporting translation initiation by leaky ribosomal scanning. This work suggests that non-canonical translation products must be examined in order to fully reveal the T cell repertoire and adds to a growing body of evidence that MHC-E-restricted T cells may have significant therapeutic value.
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