Global Analysis of the Mammalian MHC class I Immunopeptidome at the Organism-Wide Scale
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Evaluation Summary:
Kubiniok et al. use published data sets to bioinformatically study the contribution of tissue type and HLA classical class I gene allotype on the immunopeptidome, the repertoire of peptides presented by MHC class I molecules on the cell surface. This is an understudied and critically important question for understanding CD8+T cell tolerance and immunosurveillance of cancer and other diseased cells and autoimmunity, since it enables accurate prediction of peptide targets for vaccines designed to induce or suppress CD8+ T cell responses. Overall, this is a study that draws attention to some of the properties of the antigen processing and presentation pathway that had not been investigated before, namely the known differential gene expression profiles between tissues resulting in the presentation of tissue-specific antigens on HLA-I molecules, which is very valuable. Additionally this study provides avenues for investigation of the involvement of new enzymatic pathways involved in the generation of HLA-I restricted peptides that are presented to CD8+ T cells for immunosurveillance.
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Abstract
Understanding the molecular principles that govern the composition of the mammalian MHC-I immunopeptidome (MHC-Ii) across different primary tissues is fundamentally important to predict how T cell respond in different contexts in vivo . Here, we performed a global analysis of the mammalian MHC-Ii from 29 and 19 primary human and mouse tissues, respectively. First, we observed that different HLA-A, -B and -C allotypes do not contribute evenly to the global composition of the MHC-Ii across multiple human tissues. Second, we found that peptides that are presented in a tissue-dependent and -independent manner share very distinct properties. Third, we discovered that proteins that are evolutionarily hyperconserved represent the primary source of the MHC-Ii at the organism-wide scale. Finally, we uncovered new components of the antigen processing and presentation network that may drive the high level of heterogeneity of the MHC-Ii across different tissues in mammals. This study opens up new avenues toward a system-wide understanding of antigen presentation in vivo and may serve as ground work to understand tissue-dependent T cell responses in autoimmunity, infectious diseases and cancer.
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Evaluation Summary:
Kubiniok et al. use published data sets to bioinformatically study the contribution of tissue type and HLA classical class I gene allotype on the immunopeptidome, the repertoire of peptides presented by MHC class I molecules on the cell surface. This is an understudied and critically important question for understanding CD8+T cell tolerance and immunosurveillance of cancer and other diseased cells and autoimmunity, since it enables accurate prediction of peptide targets for vaccines designed to induce or suppress CD8+ T cell responses. Overall, this is a study that draws attention to some of the properties of the antigen processing and presentation pathway that had not been investigated before, namely the known differential gene expression profiles between tissues resulting in the presentation of tissue-specific …
Evaluation Summary:
Kubiniok et al. use published data sets to bioinformatically study the contribution of tissue type and HLA classical class I gene allotype on the immunopeptidome, the repertoire of peptides presented by MHC class I molecules on the cell surface. This is an understudied and critically important question for understanding CD8+T cell tolerance and immunosurveillance of cancer and other diseased cells and autoimmunity, since it enables accurate prediction of peptide targets for vaccines designed to induce or suppress CD8+ T cell responses. Overall, this is a study that draws attention to some of the properties of the antigen processing and presentation pathway that had not been investigated before, namely the known differential gene expression profiles between tissues resulting in the presentation of tissue-specific antigens on HLA-I molecules, which is very valuable. Additionally this study provides avenues for investigation of the involvement of new enzymatic pathways involved in the generation of HLA-I restricted peptides that are presented to CD8+ T cells for immunosurveillance.
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Reviewer #1 (Public Review):
Kubiniok et al. study the contribution of tissue type and HLA classical class I gene allotype on the immunopeptidome. This is an understudied and critically important question for understanding CD8+T cell tolerance and immunosurveillance of cancer and other diseased cells and autoimmunity. The study is based on published data sets obtained from different samples which compromises the analysis to some extent. Ultimately, in future studies, it will be important to determine the translatome for each tissue, as a significant fraction of peptides derive from non-annotated gene products and will be missed without this data to establish the potential immunopeptidome.
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Reviewer #2 (Public Review):
The study by Kubiniok et al. "Global analysis of the mammalian MHC class I immunopeptidome at the organism-wide scale" utilises data generated from human and mouse immunopeptidomic studies conducted by Marcu et al. (2021) and Schuster et al. (2018), respectively. These initial studies implemented immunopeptidomic profiling of an array of different organs in each species. For human HLA-I profiling, 51 different HLA-I alleles were present within the 21 subjects for which immunopeptidomic data were available, importantly covering many of the most frequently expressed HLA-I alleles globally. Using these previously generated data by the two aforementioned laboratories, Kubiniok et al. predicted restriction of peptides sequenced from each tissue type to respective HLA-I alleles from each sample using NetMHCpan4.0 …
Reviewer #2 (Public Review):
The study by Kubiniok et al. "Global analysis of the mammalian MHC class I immunopeptidome at the organism-wide scale" utilises data generated from human and mouse immunopeptidomic studies conducted by Marcu et al. (2021) and Schuster et al. (2018), respectively. These initial studies implemented immunopeptidomic profiling of an array of different organs in each species. For human HLA-I profiling, 51 different HLA-I alleles were present within the 21 subjects for which immunopeptidomic data were available, importantly covering many of the most frequently expressed HLA-I alleles globally. Using these previously generated data by the two aforementioned laboratories, Kubiniok et al. predicted restriction of peptides sequenced from each tissue type to respective HLA-I alleles from each sample using NetMHCpan4.0 - observing tissue-dependent variation in the proportion of peptides restricted by each HLA-I allele, and further stating that the affinities and abundance of both shared and tissue-specific peptides demonstrate unique properties. Finally, the authors correlate immunopeptidome findings from analysis of the 2 studies, Marcu et al. (2021) and Schuster et al. (2018), to a separate set of transcriptomic and proteomic tissue-based atlases from Geiger et al. 2013, Sollner et al. 2017, and Wang et al. 2019. They then sought to define correlations between abundance and expression of tissue-specific peptides presented on HLA-I to the tissue-specific atlases containing RNA and proteome expression data. Through their analyses, they also found that alternative components (enzymes) present in the antigen processing and presentation pathway may drive high levels of tissue-specific heterogeneity in the HLA-I-restricted immunopeptidome, thus informing targeted future experiments for investigating antigen processing.
Overall, this is a study that draws attention to some of the properties of the antigen processing and presentation pathway that had not been investigated before, namely the known differential gene expression profiles between tissues resulting in the presentation of tissue-specific antigens on HLA-I molecules, and additionally provides avenues for investigation of the involvement of new enzymatic pathways involved in the generation of HLA-I restricted peptides that are presented to CD8+ T cells for immunosurveillance (e.g. the role of the four carboxypeptidases (CPE, CNDP1, CNDP2 and CPVL).
The main points of criticism are that the tissue data has not been normalised, meaning that less material and MHC expression levels in different tissues will guide the overall sequencing depth, and therefore define the overlap of presented peptide sequences between the tissues. The bias of LC-MS acquisition towards the most abundant peptide species may further define the relationship with RNA transcript abundance. Finally, LC-MS database interpretation could lead to a bias of identifying peptides from non-variable regions if spectral interpretation did not include accurately matched personalised databases, and the conclusion that 'hyperconserved' regions are preferentially presented need very careful further validation.
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