Abstract
Mass-spectrometry based immunopeptidomics has provided unprecedented insights into antigen presentation, not only charting an enormous ligandome of self-antigens, but also cancer neoantigens and peptide antigens harbouring post-translational modifications. Here we concentrate on the latter, focusing on the small subset of HLA Class I peptides (less than 1%) that has been observed to be post-translationally modified (PTM) by a O-linked N-acetylglucosamine (GlcNAc). Just like neoantigens these modified antigens may have specific immunomodulatory functions. Here we compiled from literature, and a new dataset originating from the JY B cell lymphoblastoid cell line, a concise albeit comprehensive list of O-GlcNAcylated HLA class I peptides. This cumulative list of O-GlcNAcylated HLA peptides were derived from normal and cancerous origin, as well as tissue specimen. Remarkably, the overlap in detected O-GlcNAcylated HLA peptides as well as their source proteins is strikingly high. Most of the O-GlcNAcylated HLA peptides originate from nuclear proteins, notably transcription factors. From this list, we extract that O-GlcNAcylated HLA Class I peptides are preferentially presented by the HLA-B*07:02 allele. This allele loads peptides with a Proline residue anchor at position 2, and features a binding groove that can accommodate well the recently proposed consensus sequence for O-GlcNAcylation, P(V/A/T/S)g(S/T), essentially explaining why HLA-B*07:02 is a favoured binding allele. The observations drawn from the compiled list, may assist in the prediction of novel O-GlcNAcylated HLA antigens, which will be best presented by patients harbouring HLA-B*07:02 or related alleles that use Proline as anchoring residue.
Highlights
Peptide antigen presentation by the human leukocyte antigen (HLA) to T-cells forms an integral part of the human immune surveillance [1]
We observed substantial congruence between the glycopeptide sequences we report here and the existing datasets of Malaker et al, and Marino et al While comparing these datasets we noticed that O-GlcNAc HLA Class I peptides were presented with a marked preference by HLA-B*07:02, which harbors a Pro anchoring site for the P2 position
We first revisited the ligandome of the JY B-lymphoblastoid cell line, a model cell line used by several groups active in immunopeptidomics including ours [27, 33,34,35], as it has relative high expression of HLA complexes, and is homozygote in its HLA class I alleles, harbouring just HLA-A*02:01, HLAB*07:02, and HLA-C*07:02 alleles
Summary
Peptide antigen presentation by the human leukocyte antigen (HLA) to T-cells forms an integral part of the human immune surveillance [1]. To the peptide sequence and protein of origin, mass spectrometry can be used to identity post-translation modifications (PTMs) on the antigens. These may constitute another source of “neoantigens”, as several PTMs are recognized as hallmarks of specific diseases, including cancer and autoimmune diseases [8, 9]. Peptide antigens carrying such PTMs have been shown to affect or even regulate immune system recognition of the HLA Class I peptides [10,11,12]
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