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Edited by Peter Cresswell, Yale University School of Medicine, New Haven, CT, and approved February 13, 2014 (received for review November 15, 2013)
Significance
The surface presentation of peptides by human leukocyte antigen (HLA) class I molecules is essential for adaptive immune responses against pathogens and tumors. To date, the repertoire of HLA class I peptides remains largely unexplored, although their identity could lead to new targets for vaccine development or cancer immunotherapy. Here, we demonstrate that recent developments in mass spectrometry (MS)-based sequencing technology can expand the detectable peptide repertoire to an unprecedented depth, revealing unique features in the antigen presentation machinery. Our data include a variety of posttranslational modifications for which evidence is accumulating that they play important roles in human diseases. Hence, next-generation MS-based sequencing can make the important step into the discovery of disease-related HLA class I antigens.
Abstract
The identification of peptides presented by human leukocyte antigen (HLA) class I is tremendously important for the understanding of antigen presentation mechanisms under healthy or diseased conditions. Currently, mass spectrometry-based methods represent the best methodology for the identification of HLA class I-associated peptides. However, the HLA class I peptide repertoire remains largely unexplored because the variable nature of endogenous peptides represents difficulties in conventional peptide fragmentation technology. Here, we substantially enhanced (about threefold) the identification success rate of peptides presented by HLA class I using combined electron-transfer/higher-energy collision dissociation (EThcD), reporting over 12,000 high-confident (false discovery rate <1%) peptides from a single human B-cell line. The direct importance of such an unprecedented large dataset is highlighted by the discovery of unique features in antigen presentation. The observation that a substantial part of proteins is sampled across different HLA alleles, and the common occurrence of HLA class I nested sets, suggest that the constraints of HLA class I to comprehensively present the health states of cells are not as tight as previously thought. Our dataset contains a substantial set of peptides bearing a variety of posttranslational modifications presented with marked allele-specific differences. We propose that EThcD should become the method of choice in analyzing HLA class I-presented peptides.
- human leukocyte antigen class I
- electron-transfer dissociation
- major histocompatibility complex
- phosphorylation
- binding motif
Footnotes
- ↵1To whom correspondence should be addressed. E-mail: a.j.r.heck{at}uu.nl.
Author contributions: G.P.M.M., A.P.J.M.d.J., and A.J.R.H. designed research; G.P.M.M. and C.K.F. performed research; C.K.F., H.D.M., J.v.G.-v.d.B., C.A.C.M.v.E., and A.J.R.H. contributed new reagents/analytic tools; G.P.M.M. and C.K.F. analyzed data; and G.P.M.M., C.K.F., H.D.M., A.P.J.M.d.J., C.A.C.M.v.E., and A.J.R.H. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1321458111/-/DCSupplemental.
Expanding the detectable HLA peptidome by EThcD
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