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

Abstract

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. Here we review the discovery and analysis of CD8+ T-cell epitopes formed by protein splicing. The mechanism of protein splicing and the implications for adaptive immunity are discussed. We also highlight recently discovered spliced CD4+ T-cell epitopes that may play a role in the pathogenesis of type 1 diabetes.