Immunogenicity of Self Antigens is Unrelated to MHC-binding Affinity: T-cell Determinant Structure of Golli-MBP in the BALB/c Mouse

Maverakis, Emanual; Mendoza, Richard; Southwood, Scott; Raja-Gabaglia, Claudia; Abromson‐Leeman, Sara; Campagnoni, Anthony T.; Sette, Alessandro; Sercarz, Eli E.

doi:10.1006/jaut.2000.0436

Cited by 10 publications

(4 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Such unpredictable CD8 cell response patterns are likely to be the result of the significant variation of HLA alleles at the molecular level in any individual within the outbred human population, in conjunction with the current understanding of the rules that govern determination of CD8 epitopes (which only in part involves HLA-binding characteristics). These data are in agreement with recent studies in mice showing that the best MHC-binding CD8 epitopes are not necessarily the dominant determinants (15,16), and a study in humans suggesting that factors other than MHC binding are likely involved in defining which epitope is recognized (14). A more comprehensive approach to identifying CD8 epitopes appears necessary.…”

supporting

confidence: 91%

Comprehensive Determinant Mapping of the Hepatitis C-Specific CD8 Cell Repertoire Reveals Unpredicted Immune Hierarchy

Anthony

Valdez

Post

et al. 2002

Clinical Immunology

View full text Add to dashboard Cite

supporting

confidence: 91%

Comprehensive Determinant Mapping of the Hepatitis C-Specific CD8 Cell Repertoire Reveals Unpredicted Immune Hierarchy

Anthony

Valdez

Post

et al. 2002

Clinical Immunology

View full text Add to dashboard Cite

“…As the binding specificities of different HLA allotypes may be redundant, in the future, an exhaustive database will provide a good approximation to the definite immunopeptidome. As we know from many studies, immunogenicity of peptides is not highly correlated with binding affinity ( 26 , 58 , 59 ), and peptides with (measured) low affinity may still induce an immune response, especially upon vaccination. However, the peptides should still be naturally presented on the target cells to induce an effective T-cell response.…”

Section: Resultsmentioning

confidence: 99%

‘Hotspots’ of Antigen Presentation Revealed by Human Leukocyte Antigen Ligandomics for Neoantigen Prioritization

et al. 2017

View full text Add to dashboard Cite

The remarkable clinical efficacy of the immune checkpoint blockade therapies has motivated researchers to discover immunogenic epitopes and exploit them for personalized vaccines. Human leukocyte antigen (HLA)-binding peptides derived from processing and presentation of mutated proteins are one of the leading targets for T-cell recognition of cancer cells. Currently, most studies attempt to identify neoantigens based on predicted affinity to HLA molecules, but the performance of such prediction algorithms is rather poor for rare HLA class I alleles and for HLA class II. Direct identification of neoantigens by mass spectrometry (MS) is becoming feasible; however, it is not yet applicable to most patients and lacks sensitivity. In an attempt to capitalize on existing immunopeptidomics data and extract information that could complement HLA-binding prediction, we first compiled a large HLA class I and class II immunopeptidomics database across dozens of cell types and HLA allotypes and detected hotspots that are subsequences of proteins frequently presented. About 3% of the peptidome was detected in both class I and class II. Based on the gene ontology of their source proteins and the peptide’s length, we propose that their processing may partake by the cellular class II presentation machinery. Our database captures the global nature of the in vivo peptidome averaged over many HLA alleles, and therefore, reflects the propensity of peptides to be presented on HLA complexes, which is complementary to the existing neoantigen prediction features such as binding affinity and stability or RNA abundance. We further introduce two immunopeptidomics MS-based features to guide prioritization of neoantigens: the number of peptides matching a protein in our database and the overlap of the predicted wild-type peptide with other peptides in our database. We show as a proof of concept that our immunopeptidomics MS-based features improved neoantigen prioritization by up to 50%. Overall, our work shows that, in addition to providing huge training data to improve the HLA binding prediction, immunopeptidomics also captures other aspects of the natural in vivo presentation that significantly improve prediction of clinically relevant neoantigens.

show abstract

“…In molecular sequestration the determinants are: (A) poorly processed from the native molecule (B) have a poor binding affinity for the MHC molecules or (C) are out-competed for binding to the MHC class II molecules by a flanking determinant [21]. This can occur through competition among MHC molecules for the first available stretch of protein with a reasonably high affinity for the MHC molecule, 'determinant capture' [22].…”

Section: The Self-directed Repertoirementioning

confidence: 99%

Self-reactive T cells and Degeneracy of T Cell Recognition: Evolving Concepts—from Sequence Homology to Shape Mimicry and TCR Flexibility

Maverakis

Elzen

Sercarz

2001

Journal of Autoimmunity

Self Cite

View full text Add to dashboard Cite

Immunogenicity of Self Antigens is Unrelated to MHC-binding Affinity: T-cell Determinant Structure of Golli-MBP in the BALB/c Mouse

Cited by 10 publications

References 30 publications

Comprehensive Determinant Mapping of the Hepatitis C-Specific CD8 Cell Repertoire Reveals Unpredicted Immune Hierarchy

Comprehensive Determinant Mapping of the Hepatitis C-Specific CD8 Cell Repertoire Reveals Unpredicted Immune Hierarchy

‘Hotspots’ of Antigen Presentation Revealed by Human Leukocyte Antigen Ligandomics for Neoantigen Prioritization

Self-reactive T cells and Degeneracy of T Cell Recognition: Evolving Concepts—from Sequence Homology to Shape Mimicry and TCR Flexibility

Contact Info

Product

Resources

About