Dataset Information

The immunopeptidome presents a selected portion of the human genome with distinct features to CD8 T cells

ABSTRACT: Using proteogenomics, we identified and analyzed 25,172 major histocompatibility complex class I-associated peptides (MAPs) isolated from B lymphocytes of 18 individuals who collectively expressed 27 HLA-A,B allotypes. While 58% of genes were the source of 1-64 MAPs per gene, 42% of genes were not represented in the immunopeptidome. Overall, we estimate the immunopeptidome presented by 27 HLA-A,B allotypes covered only 17% of exomic sequences expressed in subjects’ cells. We identified several features of transcripts and proteins that enhance MAP production. From these data we built a logistic regression model that predicts with high accuracy whether a gene from our dataset or from independent datasets would generate MAPs. Our results show preferential selection of MAPs from a limited repertoire of gene products with distinct features. The notion that the immune system can monitor MAPs covering only a fraction of the protein coding genome has profound implications in autoimmunity and cancer immunology.

INSTRUMENT(S): LTQ Orbitrap Elite, Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): B Cell, Cell Culture

SUBMITTER: Courcelles Mathieu

LAB HEAD: Pierre Thibault

PROVIDER: PXD004023 | Pride | 2016-12-13

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	CELG_rep3_021213.mzid	Mzid
	CELG_rep3_021213_Fx100mM.mgf	Mgf
	CELG_rep3_021213_Fx100mM.raw	Raw
	CELG_rep3_021213_Fx300mM.mgf	Mgf
	CELG_rep3_021213_Fx300mM.raw	Raw

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Publications

MHC class I-associated peptides derive from selective regions of the human genome.

Pearson Hillary H Daouda Tariq T Granados Diana Paola DP Durette Chantal C Bonneil Eric E Courcelles Mathieu M Rodenbrock Anja A Laverdure Jean-Philippe JP Côté Caroline C Mader Sylvie S Lemieux Sébastien S Thibault Pierre P Perreault Claude C

The Journal of clinical investigation 20161114 12

MHC class I-associated peptides (MAPs) define the immune self for CD8+ T lymphocytes and are key targets of cancer immunosurveillance. Here, the goals of our work were to determine whether the entire set of protein-coding genes could generate MAPs and whether specific features influence the ability of discrete genes to generate MAPs. Using proteogenomics, we have identified 25,270 MAPs isolated from the B lymphocytes of 18 individuals who collectively expressed 27 high-frequency HLA-A,B allotype ...[more]

PMID: 27841757

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Project description:The majority of peptides presented by MHC class I results from proteasomal protein turnover. The specialized immunoproteasome, which is induced during inflammation, plays a major role in antigenic peptide generation. However, other cellular proteases can, either alone or together with the proteasome, contribute peptides for MHC class I loading non-canonically. We used an im-munopeptidomics workflow combined with a prediction software for proteasomal cleavage probabilities to analyze how inflammatory conditions affect proteasomal processing of immune epitopes presented by A549 cells. Treatment of A549 cells with IFNγ enhanced proteasomal cleavage probability of MHC class I ligands for both, the constitutive proteasome and the im-munoproteasome. Furthermore, IFNγ alters the contribution of the different HLA allotypes to the immunopeptidome. When we calculated HLA allotype-specific proteasomal cleavage probabili-ties for MHC class I ligands, peptides presented by HLA-A*30:01 showed characteristics hinting at a reduced C-terminal proteasomal cleavage probability independently of the type of proteasome. This was confirmed by HLA-A*30:01 ligands from the immune epitope database, which also showed this effect. Furthermore, two additional HLA allotypes, namely HLA-A*03:01 and HLA-A*11:01, presented peptides with a markedly reduced C-terminal proteasomal cleavage probability. Peptides eluted from all three HLA allotypes shared a peptide binding motif with a C-terminal lysine residue suggesting that this lysine residue impairs proteasome-dependent HLA ligand production and might, in turn, favor peptide generation by other cellular proteases. The mass spectrometry raw files used in this study were originally produced for a previous publication, where they were utilized to address the influence of cigarette smoke on the antiviral T-cell immune response. Here, we have reanalyzed the data to investigate processing of MHC class I ligands by c20S or i20S, respectively. Original publication: Chen, J.; Wang, X.; Schmalen, A.; Haines, S.; Wolff, M.; Ma, H.; Zhang, H.; Stoleriu, M.G.; Nowak, J.; Nakayama, M.; et al. Antiviral CD8(+) T cell immune responses are impaired by cigarette smoke and in COPD. Eur Respir J 2023, doi:10.1183/13993003.01374-2022.