Research ArticleANTIGEN PRESENTATION

A subset of HLA-I peptides are not genomically templated: Evidence for cis- and trans-spliced peptide ligands

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Science Immunology  12 Oct 2018:
Vol. 3, Issue 28, eaar3947
DOI: 10.1126/sciimmunol.aar3947

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Stitching peptides for presentation

Intracellular protein–derived peptides generated by proteasomal degradation are loaded on to class I MHC molecules in the endoplasmic reticulum and presented to CD8+ T cells. Although it has been assumed that these peptides are contiguous segments derived from intracellular proteins, recent studies have shown that noncontiguous peptides generated by cis-splicing of two distinct regions of an antigen can be presented by class I MHC molecules. Here, Faridi et al. demonstrate that class I MHC molecules can present peptides that are generated by splicing together of segments from two distinct proteins and term them to be “trans-spliced” peptides. Precisely how cis- and trans-spliced peptides are generated and how they contribute to T cell selection and expansion remain to be explored.

Abstract

The diversity of peptides displayed by class I human leukocyte antigen (HLA) plays an essential role in T cell immunity. The peptide repertoire is extended by various posttranslational modifications, including proteasomal splicing of peptide fragments from distinct regions of an antigen to form nongenomically templated cis-spliced sequences. Previously, it has been suggested that a fraction of the immunopeptidome constitutes such cis-spliced peptides; however, because of computational limitations, it has not been possible to assess whether trans-spliced peptides (i.e., the fusion of peptide segments from distinct antigens) are also bound and presented by HLA molecules, and if so, in what proportion. Here, we have developed and applied a bioinformatic workflow and demonstrated that trans-spliced peptides are presented by HLA-I, and their abundance challenges current models of proteasomal splicing that predict cis-splicing as the most probable outcome. These trans-spliced peptides display canonical HLA-binding sequence features and are as frequently identified as cis-spliced peptides found bound to a number of different HLA-A and HLA-B allotypes. Structural analysis reveals that the junction between spliced peptides is highly solvent exposed and likely to participate in T cell receptor interactions. These results highlight the unanticipated diversity of the immunopeptidome and have important implications for autoimmunity, vaccine design, and immunotherapy.

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