MHC Class I Immunopeptidome: Past, Present, and Future

Yewdell, Jonathan W.

doi:10.1016/j.mcpro.2022.100230

Cited by 44 publications

(25 citation statements)

References 121 publications

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“…First of all, 'what happens where' during the class I presentation, was assumed to be known, thus in situ localization of MHC-I has just not been studied. A recent focus was more on finding out what are the peptides presented on MHC-I molecules for T cells immunosurveillance [21]. These studies rely on the w6/32 antibody that recognises a conformational epitope of an assembled MHC-I molecule, but w6/32 cannot really be used in fixed (cross-linked) cells, in which the conformational epitope might have been perturbed.…”

Section: Discussionmentioning

confidence: 99%

Major Histocompatibility Complex class I heavy chains localize in both cytoplasmic and nuclear compartment

Gómez-Herranz

Dziadosz

Mikac

et al. 2022

Preprint

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The Major Histocompatibility Complex class I (MHC-I) molecules present antigenic peptides (AP) to CD8+ T cells for self versus non-self recognition. Loading of AP on MHC-I takes place in the endoplasmic reticulum (ER), upon shuttling of cytoplasmic AP substrates to the ER. Understanding of this process has been influenced by the view that MHC-I antigens are produced from the proteasomal degradation of cellular proteins. Recent observations on the intronic and untranslated region-derived peptides as well as on the non-AUG translation products presented on the MHC-I open the possibility that antigenic peptides can derive from pre-spliced mRNAs translated in the nuclear compartment. In this brief report, we show that a fraction of human MHC-I molecules (human leukocyte antigens type A, HLA-A) is present in the nuclei of cells, in the proximity of histone H2B. With this finding, we hope to initiate a new direction of research on the nuclear role of MHC-I and ask whether the loading of antigens can take place in the nuclear compartment.

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Section: Discussionmentioning

confidence: 99%

Major Histocompatibility Complex class I heavy chains localize in both cytoplasmic and nuclear compartment

Gómez-Herranz

Dziadosz

Mikac

et al. 2022

Preprint

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“…The non-linearly templated peptides increase the diversity of target peptides for recognition by T cells and possibly create a particular risk of escaping tolerance mechanisms and triggering autoimmunity. Three types of peptides therefore need to be considered for the identification of immunogenic HLA-presented self-peptides of autoimmune reactions: peptides with true linear sequences > nonlinearly templated peptides including spliced peptides > untemplated peptides with no current biological explanation ( 64 ).…”

Section: Hla-alleles T-cell Antigen Recognition and Immunopeptidomesmentioning

confidence: 99%

Immunogenic self-peptides - the great unknowns in autoimmunity: Identifying T-cell epitopes driving the autoimmune response in autoimmune diseases

Prinz

2023

Front. Immunol.

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HLA-associated autoimmune diseases likely arise from T-cell-mediated autoimmune responses against certain self-peptides from the broad HLA-presented immunopeptidomes. The limited knowledge of the autoimmune target peptides has so far compromised the basic understanding of autoimmune pathogenesis. This is due to the complexity of antigen processing and presentation as well as the polyspecificity of T-cell receptors (TCRs), which pose high methodological challenges on the discovery of immunogenic self-peptides. HLA-class I molecules present peptides to CD8+ T cells primarily derived from cytoplasmic proteins. Therefore, HLA-class I-restricted autoimmune responses should be directed against target cells expressing the corresponding parental protein. In HLA-class II-associated diseases, the origin of immunogenic peptides is not pre-specified, because peptides presented by HLA-class II molecules to CD4+ T cells may originate from both extracellular and cellular self-proteins. The different origins of HLA-class I and class II presented peptides determine the respective strategy for the discovery of immunogenic self-peptides in approaches based on the TCRs isolated from clonally expanded pathogenic T cells. Both involve identifying the respective restricting HLA allele as well as determining the recognition motif of the TCR under investigation by peptide library screening, which is required to search for homologous immunogenic self-peptides. In HLA-class I-associated autoimmune diseases, identification of the target cells allows for defining the restricting HLA allotype from the 6 different HLA-class I alleles of the individual HLA haplotype. It furthermore limits the search for immunogenic self-peptides to the transcriptome or immunopeptidome of the target cells, although neoepitopes generated by peptide splicing or translational errors may complicate identification. In HLA class II-associated autoimmune diseases, the lack of a defined target cell and differential antigen processing in different antigen-presenting cells complicate identification of the HLA restriction of autoreactive TCRs from CD4+ T cells. To avoid that all corresponding HLA-class II allotypes have to be included in the peptide discovery, autoantigens defined by autoantibodies can guide the search for immunogenic self-peptides presented by the respective HLA-class II risk allele. The objective of this article is to highlight important aspects to be considered in the discovery of immunogenic self-peptides in autoimmune diseases.

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“…Since the early days of profiling the immunopeptidome using mass spectrometry (MS) some three decades ago [ 11 ], there has been substantial improvement in the overall approach, including the application of machine learning [ 12 , 13 , 14 ]. The detection and prediction of immunogenic peptides through genomic and transcriptomic data is challenging and overlooks protein aberrations that occur after transcription.…”

Section: Introductionmentioning

confidence: 99%

Mining the Immunopeptidome for Antigenic Peptides in Cancer

León‐Letelier

Katayama

Hanash

2022

Cancers

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Although harnessing the immune system for cancer therapy has shown success, response to immunotherapy has been limited. The immunopeptidome of cancer cells presents an opportunity to discover novel antigens for immunotherapy applications. These neoantigens bind to MHC class I and class II molecules. Remarkably, the immunopeptidome encompasses protein post-translation modifications (PTMs) that may not be evident from genome or transcriptome profiling. A case in point is citrullination, which has been demonstrated to induce a strong immune response. In this review, we cover how the immunopeptidome, with a special focus on PTMs, can be utilized to identify cancer-specific antigens for immunotherapeutic applications.

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MHC Class I Immunopeptidome: Past, Present, and Future

Cited by 44 publications

References 121 publications

Major Histocompatibility Complex class I heavy chains localize in both cytoplasmic and nuclear compartment

Major Histocompatibility Complex class I heavy chains localize in both cytoplasmic and nuclear compartment

Immunogenic self-peptides - the great unknowns in autoimmunity: Identifying T-cell epitopes driving the autoimmune response in autoimmune diseases

Mining the Immunopeptidome for Antigenic Peptides in Cancer

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