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Predicting Antigen Presentation-What Could We Learn From a Million Peptides?

ABSTRACT: Antigen presentation lies at the heart of immune recognition of infected or malignant cells. For this reason, important efforts have been made to predict which peptides are more likely to bind and be presented by the human leukocyte antigen (HLA) complex at the surface of cells. These predictions have become even more important with the advent of next-generation sequencing technologies that enable researchers and clinicians to rapidly determine the sequences of pathogens (and their multiple variants) or identify non-synonymous genetic alterations in cancer cells. Here, we review recent advances in predicting HLA binding and antigen presentation in human cells. We argue that the very large amount of high-quality mass spectrometry data of eluted (mainly self) HLA ligands generated in the last few years provides unprecedented opportunities to improve our ability to predict antigen presentation and learn new properties of HLA molecules, as demonstrated in many recent studies of naturally presented HLA-I ligands. Although major challenges still lie on the road toward the ultimate goal of predicting immunogenicity, these experimental and computational developments will facilitate screening of putative epitopes, which may eventually help decipher the rules governing T cell recognition.

SUBMITTER: Gfeller D

PROVIDER: S-EPMC6068240 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Predicting Antigen Presentation-What Could We Learn From a Million Peptides?

Gfeller David D Bassani-Sternberg Michal M

Frontiers in immunology 20180725

Antigen presentation lies at the heart of immune recognition of infected or malignant cells. For this reason, important efforts have been made to predict which peptides are more likely to bind and be presented by the human leukocyte antigen (HLA) complex at the surface of cells. These predictions have become even more important with the advent of next-generation sequencing technologies that enable researchers and clinicians to rapidly determine the sequences of pathogens (and their multiple vari ...[more]

PMID: 30090105

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Project description:Accurate predictions of T-cell epitopes would be useful for designing vaccines, immunotherapies for cancer and autoimmune diseases, and improved protein therapies. The humoral immune response involves uptake of antigens by antigen presenting cells (APCs), APC processing and presentation of peptides on MHC class II (pMHCII), and T-cell receptor (TCR) recognition of pMHCII complexes. Most in silico methods predict only peptide-MHCII binding, resulting in significant over-prediction of CD4 T-cell epitopes. We present a method, ITCell, for prediction of T-cell epitopes within an input protein antigen sequence for given MHCII and TCR sequences. The method integrates information about three stages of the immune response pathway: antigen cleavage, MHCII presentation, and TCR recognition. First, antigen cleavage sites are predicted based on the cleavage profiles of cathepsins S, B, and H. Second, for each 12-mer peptide in the antigen sequence we predict whether it will bind to a given MHCII, based on the scores of modeled peptide-MHCII complexes. Third, we predict whether or not any of the top scoring peptide-MHCII complexes can bind to a given TCR, based on the scores of modeled ternary peptide-MHCII-TCR complexes and the distribution of predicted cleavage sites. Our benchmarks consist of epitope predictions generated by this algorithm, checked against 20 peptide-MHCII-TCR crystal structures, as well as epitope predictions for four peptide-MHCII-TCR complexes with known epitopes and TCR sequences but without crystal structures. ITCell successfully identified the correct epitopes as one of the 20 top scoring peptides for 22 of 24 benchmark cases. To validate the method using a clinically relevant application, we utilized five factor VIII-specific TCR sequences from hemophilia A subjects who developed an immune response to factor VIII replacement therapy. The known HLA-DR1-restricted factor VIII epitope was among the six top-scoring factor VIII peptides predicted by ITCall to bind HLA-DR1 and all five TCRs. Our integrative approach is more accurate than current single-stage epitope prediction algorithms applied to the same benchmarks. It is freely available as a web server (http://salilab.org/itcell).

Project description:BackgroundMesenchymal stromal cells (MSCs) have been extensively used in the clinic due to their exquisite tissue repair capacity. However, they also hold promise in the field of cellular vaccination as they can behave as conditional antigen presenting cells in response to interferon (IFN)-gamma treatment under a specific treatment regimen. This suggests that the immune function of MSCs can be pharmacologically modulated. Given the capacity of the agonist pyrimido-indole derivative UM171a to trigger the expression of various antigen presentation-related genes in human hematopoietic progenitor cells, we explored the potential use of UM171a as a means to pharmacologically instill and/or promote antigen presentation by MSCs.MethodsBesides completing a series of flow-cytometry-based phenotypic analyses, several functional antigen presentation assays were conducted using the SIINFEKL-specific T-cell clone B3Z. Anti-oxidants and electron transport chain inhibitors were also used to decipher UM171a's mode of action in MSCs. Finally, the potency of UM171a-treated MSCs was evaluated in the context of therapeutic vaccination using immunocompetent C57BL/6 mice with pre-established syngeneic EG.7T-cell lymphoma.ResultsTreatment of MSCs with UM171a triggered potent increase in H2-Kb cell surface levels along with the acquisition of antigen cross-presentation abilities. Mechanistically, such effects occurred in response to UM171a-mediated production of mitochondrial-derived reactive oxygen species as their neutralization using anti-oxidants or Antimycin-A mitigated MSCs' ability to cross-present antigens. Processing and presentation of the immunogenic ovalbumin-derived SIINFEKL peptide was caused by de novo expression of the Psmb8 gene in response to UM171a-triggered oxidative stress. When evaluated for their anti-tumoral properties in the context of therapeutic vaccination, UM171a-treated MSC administration to immunocompetent mice with pre-established T-cell lymphoma controlled tumor growth resulting in 40% survival without the need of additional supportive therapy and/or standard-of-care.ConclusionsAltogether, our findings reveal a new immune-related function for UM171a and clearly allude to a direct link between UM171a-mediated ROS induction and antigen cross-presentation by MSCs. The fact that UM171a treatment modulates MSCs to become antigen-presenting cells without the use of IFN-gamma opens-up a new line of investigation to search for additional agents capable of converting immune-suppressive MSCs to a cellular tool easily adaptable to vaccination.

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Predicting Antigen Presentation-What Could We Learn From a Million Peptides?

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Predicting Antigen Presentation-What Could We Learn From a Million Peptides?

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