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

Journal article


Faridi, Pouya, Li, Chen, Ramarathinam, Sri H., Vivian, Julian P., Illing, Patricia T., Mifsud, Nicole A., Ayala, Rochelle, Song, Jiangning, Gearing, Linden J., Hertzog, Paul J., Ternette, Nicola, Rossjohn, Jamie, Croft, Nathan P. and Purcell, Anthony W.. (2018). A subset of HLA-I peptides are not genomically templated : Evidence for cis- and trans-spliced peptide ligands. Science Immunology. 3(28), p. Article eaar3947. https://doi.org/10.1126/sciimmunol.aar3947
AuthorsFaridi, Pouya, Li, Chen, Ramarathinam, Sri H., Vivian, Julian P., Illing, Patricia T., Mifsud, Nicole A., Ayala, Rochelle, Song, Jiangning, Gearing, Linden J., Hertzog, Paul J., Ternette, Nicola, Rossjohn, Jamie, Croft, Nathan P. and Purcell, Anthony W.
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.

Year2018
JournalScience Immunology
Journal citation3 (28), p. Article eaar3947
PublisherAmerican Association for the Advancement of Science
ISSN2470-9468
Digital Object Identifier (DOI)https://doi.org/10.1126/sciimmunol.aar3947
PubMed ID30315122
Scopus EID2-s2.0-85054891092
Open accessPublished as green open access
Page range1-11
FunderNational Health and Medical Research Council (NHMRC)
Australian Research Council (ARC)
Author's accepted manuscript
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All rights reserved
File Access Level
Open
Publisher's version
License
All rights reserved
File Access Level
Controlled
Output statusPublished
Publication dates
Online12 Oct 2018
Publication process dates
Accepted31 Aug 2018
Deposited28 Nov 2023
ARC Funded ResearchThis output has been funded, wholly or partially, under the Australian Research Council Act 2001
Grant ID1085017
1084283
DP150104503
1137739
1143366
1072159
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