Shuffling peptides to create T-cell epitopes: does the immune system play cards?

For a long time, immunologists have believed that classical CD4⁺ and CD8⁺ T cells recognize peptides (referred to as epitopes), derived from protein antigens presented by MHC/HLA class I or II. Over the past 10-15 years, it has become clear that epitopes recognized by CD8⁺, and more recently CD4⁺ T cells, can be formed by protein splicing. Here, we review the discovery of spliced epitopes recognized by tumor-specific human CD8⁺ T cells. We discuss how these epitopes are formed and some of the unusual variants that have been reported. Now, over a decade since the first report, evidence is emerging that spliced CD8⁺ T-cell epitopes are much more common, and potentially much more important, than previously imagined. Recent work has shown that epitopes recognized by CD4⁺ T cells can also be formed by protein splicing. We discuss the recent discovery of spliced CD4⁺ T-cell epitopes and their potential role as targets of autoimmune T-cell responses. Finally, we highlight some of the new questions raised from our growing appreciation of T-cell epitopes formed by peptide splicing.