Summary

Title

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

Description

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.

Sample Processing Protocol

MAPs were eluted from B-LCL and sequenced by mass spectrometry as previously described : Granados,D.P. et al. Impact of genomic polymorphism on the repertoire of human MHC class I-associated peptides. Nat Commun 5, 3600 (2014) & Granados,D.P. et al. Proteogenomic-based discovery of minor histocompatibility antigens with suitable features for immunotherapy of hematologic cancers. Leukemia (2016)

Data Processing Protocol

Peptides were identified with PEAKS®7 using subject-specific sequence databases. The following parameters were used for each search: mass tolerances for precursor ( 5 p.p.m.), fragment ions (0.02 Da), no enzyme specificity, variable modifications cysteinylation, phosphorylation (Ser, Thr and Tyr), oxidation (Met) and deamidation (Asn, Gln).

Contact

Courcelles Mathieu, IRIC
Pierre Thibault, Institute for Research in Immunology and Cancer, Department of Biochemistry, Department of Chemistry, Université de Montréal, Québec, Canada H3T 1J4 ( lab head )

Submission Date

20/04/2016

Publication Date

13/12/2016

Publication

    Pearson H, Daouda T, Granados DP, Durette C, Bonneil E, Courcelles M, Rodenbrock A, Laverdure JP, Côté C, Mader S, Lemieux S, Thibault P, Perreault C. MHC class I-associated peptides derive from selective regions of the human genome. J Clin Invest. 2016 Dec 1;126(12):4690-4701 PubMed: 27841757