T cell receptor fingerprinting enables in-depth characterization of the interactions governing recognition of peptide–MHC complexes

Bentzen, Amalie Kai; Such, Lina; Jensen, Kamilla Kjærgaard; Marquard, Andrea Marion; Jessen, Leon Eyrich; Miller, Natalie J.; Church, Candice D.; Lyngaa, Rikke; Koelle, David M.; Becker, Jürgen C.; Linnemann, Carsten; Schumacher, Ton N.; Marcatili, Paolo; Nghiem, Paul; Nielsen, Morten; Hadrup, Sine Reker

doi:10.1038/nbt.4303

Cited by 83 publications

(83 citation statements)

References 52 publications

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“…We have also shown that the other CDRs in addition to CDR3β can provide useful information for the classification task and that it can depend on the epitope in question which of the CDRs are important. The currently available sequence data of epitope-specific TCRs has allowed us to come this far, but it will be interesting to see what can be achieved when more data becomes available with modern high-throughput techniques presented recently (Bentzen et al, 2018;Zhang et al, 2018). Because of the limited data, we have not yet been able to consider the similarities of the epitopes and the significance of the different HLA-types of the MHC proteins presenting the epitopes.…”

Section: Discussionmentioning

confidence: 99%

Determining epitope specificity of T cell receptors with TCRGP

Jokinen

Huuhtanen

Mustjoki

et al. 2019

Preprint

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T cell receptors (TCRs) can recognize various pathogens and consequently start immune responses. TCRs can be sequenced from individuals and methods that can analyze the specificity of the TCRs can help us better understand the individual's immune status in different diseases. We have developed TCRGP, a novel Gaussian process (GP) method that can predict if TCRs recognize certain epitopes. This method can utilize different CDR sequences from both TCRα and TCRβ chains from single-cell data and learn which CDRs are important in recognizing the different epitopes. We have experimented with one previously presented and one new data set and show that TCRGP outperforms other state-of-the-art methods in predicting the epitope specificity of TCRs on both data sets. The software implementation and data sets are available at https://github.com/emmijokinen/TCRGP.

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Section: Discussionmentioning

confidence: 99%

Determining epitope specificity of T cell receptors with TCRGP

Jokinen

Huuhtanen

Mustjoki

et al. 2019

Preprint

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“…23,[25][26][27][28][29][30][31] Moreover, several studies have revealed that TCR contact conservation in peptide antigens contributes to cross-reactivity. 29,32,33 One conserved anchoring amino acid associated with two or more conserved TCR-contacting amino acids within a core nonamer is sufficient to enable two different MHC II-binding peptides to cross-react with the same TCR. 29,34 Similarly, an MHC I-restricted CD8 T-cell TCR can cross-react with altered peptide antigens harbouring one or two substitutions in the TCR contact positions.…”

Section: Neoantigen Immunogenicity and T-cell Recognitionmentioning

confidence: 99%

Pre‐existing heterologous T‐cell immunity and neoantigen immunogenicity

et al. 2020

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Neoantigens are tumor‐specific mutated proteins that are exempt from central tolerance and are therefore capable of efficiently eliciting effective T‐cell responses. The identification of immunogenic neoantigens in tumor‐specific mutated proteins has promising clinical implications for cancer immunotherapy. However, the factors that may contribute to neoantigen immunogenicity are not yet fully understood. Through molecular mimicry of antigens arising during cancer progression, the gut microbiota and previously encountered pathogens potentially have profound impacts on T‐cell responses to previously unencountered tumor neoantigens. Here, we review the characteristics of immunogenic neoantigens and how host exposure to microbes may affect T‐cell responses to neoantigens. We address the hypothesis that pre‐existing heterologous memory T‐cell immunity is a major factor that influences neoantigen immunogenicity in individual cancer patients. Accumulating data suggest that differences in individual histories of microbial exposure should be taken into account during the optimisation of algorithms that predict neoantigen immunogenicity.

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“…On the horizon, single cell RNA-sequencing (RNA-seq) technologies have the potential to revolutionize the study of antigen-specific immune cells (75,76). The ability to generate a library of tetramers with unique barcodes could allow the simultaneous examination of gene expression profiles from a large number of cells with different antigen specificities in a single experiment.…”

Section: Emerging Techniques For Studying Antigen-specific Primary B mentioning

confidence: 99%

Techniques to Study Antigen-Specific B Cell Responses

Boonyaratanakornkit

Taylor

2019

Front. Immunol.

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Antibodies against foreign antigens are a critical component of the overall immune response and can facilitate pathogen clearance during a primary infection and also protect against subsequent infections. Dysregulation of the antibody response can lead to an autoimmune disease, malignancy, or enhanced infection. Since the experimental delineation of a distinct B cell lineage in 1965, various methods have been developed to understand antigen-specific B cell responses in the context of autoimmune diseases, primary immunodeficiencies, infection, and vaccination. In this review, we summarize the established techniques and discuss new and emerging technologies for probing the B cell response in vitro and in vivo by taking advantage of the specificity of B cell receptor (BCR)-associated and secreted antibodies. These include ELISPOT, flow cytometry, mass cytometry, and fluorescence microscopy to identify and/or isolate primary antigen-specific B cells. We also present our approach to identify rare antigen-specific B cells using magnetic enrichment followed by flow cytometry. Once these cells are isolated, in vitro proliferation assays and adoptive transfer experiments in mice can be used to further characterize antigen-specific B cell activation, function, and fate. Transgenic mouse models of B cells targeting model antigens and of B cell signaling have also significantly advanced our understanding of antigen-specific B cell responses in vivo .

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T cell receptor fingerprinting enables in-depth characterization of the interactions governing recognition of peptide–MHC complexes

Cited by 83 publications

References 52 publications

Determining epitope specificity of T cell receptors with TCRGP

Determining epitope specificity of T cell receptors with TCRGP

Pre‐existing heterologous T‐cell immunity and neoantigen immunogenicity

Techniques to Study Antigen-Specific B Cell Responses

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