The unbearable lightness of being an unconventional spliced epitope

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Keywords:
proteasomes, peptide splicing, antigens, proteomics, tolerance

In the last two decades researchers discovered that antigenic peptides presented by MHC class I and II molecules are not only conventional peptides derived from portion of proteins, but also unconventional peptides. Latter can derive from putative non-coding regions of the genome (cryptic peptides) or from post-translational modifications of proteins and polypeptides. For example, proteases can re-shuffle protein sequences and release functional “spliced” peptides. The most studied spliced peptides are those generated by proteasomes and presented on HLA class I molecules to CD8+ T cells although spliced epitopes presented by HLA class II complexes and associated to Type 1 Diabetes have been discovered.

Identification of unconventional spliced epitopes is challenging and is carried out through a multidisciplinary strategy containing in silico, biochemical, proteomics, molecular and cellular immunology and ex vivo/in vivo techniques, which have been developed by us and other groups. Spliced epitopes have been demonstrated to play a role in the immune response in cancer, infection and autoimmunity, although the frequency and immunological relevance of spliced peptides is the subject of an intense controversy. Recent in silico studies of our groups suggest that proteasomegenerated spliced peptides may not be in contrast with our model of central and peripheral tolerance. Despite the controversy in the proteomics field, post-translationally spliced epitopes can represent a suitable target for immunotherapies.