What we learned on peptide splicing in the last 2 years

Abstract

Proteasomes are the main producers of the epitopes presented on MHC-I molecules to CD8+ T cells. The epitopes could be produced by peptide-bond hydrolysis or by proteasome-catalysed peptide splicing, which are driven by partially different factors. The frequency and immunological relevance of spliced peptides has been a bellicose matter of debate in the last few years. Some studies show that spliced peptides represent around 20-30% of the MHC-I immunopeptidomes. They extend the antigenic landscape of tumour and non-tumour cells to antigens that otherwise would be neglected by the immune system. These antigens are preferentially longer, more hydrophobic and basic than those represented by non-spliced peptides. The immunological relevance of proteasome-generated spliced epitopes in cancer is known since their discovery in 2004 and it has been further confirmed by recent outcomes. In addition, in the last few years, their recognition by CD8+ T cells in Type 1 Diabetes patients and during Listeria monocytogenes infection has also been demonstrated. Therefore, more and more evidences suggest that spliced epitopes can be targets of immunotherapies against cancer, autoimmunity and infections exploiting the theoretical large spliced peptide sequence variety.