scholarly journals TCRMatch: Predicting T-Cell Receptor Specificity Based on Sequence Similarity to Previously Characterized Receptors

2021 ◽  
Vol 12 ◽  
Author(s):  
William D. Chronister ◽  
Austin Crinklaw ◽  
Swapnil Mahajan ◽  
Randi Vita ◽  
Zeynep Koşaloğlu-Yalçın ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
High Throughput Sequencing ◽  
Sequence Similarity ◽  
Adaptive Immune System ◽  
Cell Receptor ◽  
Epitope Specificity ◽  
Receptor Repertoire ◽  
Tcr Repertoire ◽  
Specific Receptors

The adaptive immune system in vertebrates has evolved to recognize non-self antigens, such as proteins expressed by infectious agents and mutated cancer cells. T cells play an important role in antigen recognition by expressing a diverse repertoire of antigen-specific receptors, which bind epitopes to mount targeted immune responses. Recent advances in high-throughput sequencing have enabled the routine generation of T-cell receptor (TCR) repertoire data. Identifying the specific epitopes targeted by different TCRs in these data would be valuable. To accomplish that, we took advantage of the ever-increasing number of TCRs with known epitope specificity curated in the Immune Epitope Database (IEDB) since 2004. We compared seven metrics of sequence similarity to determine their power to predict if two TCRs have the same epitope specificity. We found that a comprehensive k-mer matching approach produced the best results, which we have implemented into TCRMatch, an openly accessible tool (http://tools.iedb.org/tcrmatch/) that takes TCR β-chain CDR3 sequences as an input, identifies TCRs with a match in the IEDB, and reports the specificity of each match. We anticipate that this tool will provide new insights into T cell responses captured in receptor repertoire and single cell sequencing experiments and will facilitate the development of new strategies for monitoring and treatment of infectious, allergic, and autoimmune diseases, as well as cancer.

scholarly journals TCRMatch: Predicting T-cell receptor specificity based on sequence similarity to previously characterized receptors

2020 ◽  
Author(s):  
William D Chronister ◽  
Austin Crinklaw ◽  
Swapnil Mahajan ◽  
Randi Vita ◽  
Zeynep Kosaloglu-Yalcin ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
High Throughput Sequencing ◽  
Sequence Similarity ◽  
Adaptive Immune System ◽  
Cell Receptor ◽  
Epitope Specificity ◽  
Receptor Repertoire ◽  
Tcr Repertoire ◽  
Specific Receptors

The adaptive immune system in vertebrates has evolved to recognize non-self-antigens, such as proteins expressed by infectious agents and mutated cancer cells. T cells play an important role in antigen recognition by expressing a diverse repertoire of antigen-specific receptors, which bind epitopes to mount targeted immune responses. Recent advances in high-throughput sequencing have enabled the routine generation of T-cell receptor (TCR) repertoire data. Identifying the specific epitopes targeted by different TCRs in these data would be valuable. To accomplish that, we took advantage of the ever-increasing number of TCRs with known epitope specificity curated in the Immune Epitope Database (IEDB) since 2004. We compared six metrics of sequence similarity to determine their power to predict if two TCRs have the same epitope specificity. We found that a comprehensive k-mer matching approach produced the best results, which we have implemented into TCRMatch, an openly accessible tool (http://tools.iedb.org/tcrmatch/) that takes TCR β-chain CDR3 sequences as an input, identifies TCRs with a match in the IEDB, and reports the specificity of each match. We anticipate that this tool will provide new insights into T cell responses captured in receptor repertoire and single cell sequencing experiments and will facilitate the development of new strategies for monitoring and treatment of infectious, allergic, and autoimmune diseases, as well as cancer.

scholarly journals Immunosenescence and Autoimmunity: Exploiting the T-Cell Receptor Repertoire to Investigate the Impact of Aging on Multiple Sclerosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Roberta Amoriello ◽  
Alice Mariottini ◽  
Clara Ballerini
Keyword(s):  
Multiple Sclerosis ◽  
T Cell ◽  
T Cell Receptor ◽  
High Throughput Sequencing ◽  
Cell Receptor ◽  
Receptor Repertoire ◽  
Age Related ◽  
Tcr Repertoire ◽  
Repertoire Diversity ◽  
The Impact

T-cell receptor (TCR) repertoire diversity is a determining factor for the immune system capability in fighting infections and preventing autoimmunity. During life, the TCR repertoire diversity progressively declines as a physiological aging progress. The investigation of TCR repertoire dynamics over life represents a powerful tool unraveling the impact of immunosenescence in health and disease. Multiple Sclerosis (MS) is a demyelinating, inflammatory, T-cell mediated autoimmune disease of the Central Nervous System in which age is crucial: it is the most widespread neurological disease among young adults and, furthermore, patients age may impact on MS progression and treatments outcome. Crossing knowledge on the TCR repertoire dynamics over MS patients’ life is fundamental to investigate disease mechanisms, and the advent of high- throughput sequencing (HTS) has significantly increased our knowledge on the topic. Here we report an overview of current literature about the impact of immunosenescence and age-related TCR dynamics variation in autoimmunity, including MS.

scholarly journals T cell receptor repertoire for a viral epitope in humans is diversified by tolerance to a background major histocompatibility complex antigen.

1995 ◽  
Vol 182 (6) ◽  
pp. 1703-1715 ◽  
Author(s):  
S R Burrows ◽  
S L Silins ◽  
D J Moss ◽  
R Khanna ◽  
I S Misko ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Specific Response ◽  
Major Histocompatibility ◽  
Antigen Receptors ◽  
Barr Virus ◽  
Receptor Repertoire ◽  
Tcr Repertoire ◽  
Epstein Barr

Two unusual characteristics of the memory response to the immunodominant Epstein-Barr virus (EBV) epitope FLRGRAYGL, which associates with HLA B8, have provided an unique opportunity to investigate self tolerance and T cell receptor (TCR) plasticity in humans. First, the response is exceptionally restricted, dominated by cytotoxic T lymphocytes (CTL) with identical TCR protein sequences (Argaet, V. P., C. W. Schmidt, S. R. Burrows, S. L. Silins, M. G. Kurilla, D. L. Doolan, A. Suhrbier, D. J. Moss, E. Kieff, T. B. Sculley, and I. S. Misko. 1994. J. Exp. Med. 180:2335-2340). Second, CTL expressing this receptor are cross-reactive with the alloantigen HLA B* 4402 on uninfected cells (Burrows, S. R., R. Khanna, J. M. Burrows, and D. J. Moss. 1994. J. Exp. Med. 179:1155-1161). No CTL using this conserved public TCR could be reactivated from the peripheral blood of EBV exposed individuals expressing both HLA B8 and B*4402, demonstrating the clonal inactivation of potentially self-reactive T cells in humans. A significant FLRGRAYGL-specific response was still apparent, however, and TCR sequence analysis of multiple CTL clones revealed an oligoclonal TCR repertoire for this determinant within these individuals, using diverse V and J gene segments and CDR3 regions. In addition, a significant public TCR component was identified in which several distinct alpha/beta rearrangements are shared by CTL clones from a number of unrelated HLA B8+, B*4402+ donors. The striking dominance of public TCR in the response to this EBV epitope suggests a strong genetic bias in TCR gene recombination. Fine specificity analysis using peptide analogues showed that, of six different antigen receptors for FLRGRAYGL/HLA B8, none associate closely with the peptide's full array of potential TCR contact residues. Whereas the HLA B*4402-cross-reactive receptor binds amino acids toward the COOH terminus of the peptide, others preferentially favor an NH2-terminal determinant, presumably evading an area that mimics a structure presented on HLA B*4402. Thus, tolerance to a background major histocompatibility antigen can effectively diversify the TCR repertoire for a foreign epitope by deflecting the response away from an immunodominant combination of TCR-binding residues.

scholarly journals T-cell receptor αβ chain pairing is associated with CD4+ and CD8+ lineage specification

2018 ◽  
Author(s):  
Jason A. Carter ◽  
Jonathan B. Preall ◽  
Kristina Grigaityte ◽  
Stephen J. Goldfless ◽  
Adrian W. Briggs ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Human Subjects ◽  
Cell Lineage ◽  
Adaptive Immune System ◽  
Cell Receptor ◽  
Lineage Specification ◽  
Cdr3 Length ◽  
Tcr Repertoire ◽  
Strength Of Association

AbstractWhile a highly diverse T-cell receptor (TCR) repertoire is the hallmark of a healthy adaptive immune system, relatively little is understood about how the CD4+ and CD8+ TCR repertoires differ from one another. We here utilize high-throughput single T-cell sequencing to obtain approximately 100,000 TCR αβ chain pairs from human subjects, stratified into CD4+ and CD8+ lineages. We reveal that substantial information about T-cell lineage is encoded by Vαβ gene pairs and, to a lesser extent, by several other TCR features such as CDR3 length and charge. We further find that the strength of association between the β chain and T-cell lineage is surprisingly weak, similar in strength to that of the α chain. Using machine learning classifiers to predict T-cell lineage from TCR features, we demon-strate that αβ chain pairs are significantly more informative than individual chains alone. These findings provide unprecedented insight into the CD4+ and CD8+ TCR repertoires and highlight the importance of αβ chain pairing in TCR function and specificity.

scholarly journals High throughput sequencing of T-cell receptor repertoire using dry blood spots

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Shang-Gin Wu ◽  
Wenjing Pan ◽  
Hongna Liu ◽  
Miranda L. Byrne-Steele ◽  
Brittany Brown ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
High Throughput ◽  
High Throughput Sequencing ◽  
Cell Receptor ◽  
Blood Spots ◽  
Receptor Repertoire ◽  
T Cell Receptor Repertoire ◽  
Cell Receptor Repertoire

scholarly journals Ancestry diversity of open T-cell receptor repertoire data, a systematic assessment

2021 ◽  
Author(s):  
Yu Ning Huang ◽  
Kerui Peng ◽  
SERGHEI MANGUL
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
High Throughput ◽  
High Throughput Sequencing ◽  
Cell Receptor ◽  
Cell Receptors ◽  
Systematic Assessment ◽  
Bioinformatic Tools ◽  
Sequencing Technologies ◽  
Receptor Repertoire

Recent advancement from low-throughput sequencing techniques to high-throughput sequencing gives the public more efficient ways to acquire human adaptive immune receptor repertoire sequences (AIRR-seq). The advanced high-throughput sequencing techniques allow scientists to comprehensively examine and characterize the T cell receptors’ and B cell receptors’ genetic sequences efficiently. The development of multi-powerful platforms in AIRR-seq studies and advanced bioinformatic tools also boosts the AIRR community’s richness. However, although high-throughput sequencing technologies have been well-developed, most AIRR-seq studies have not taken ancestries or populations in their research into consideration. In the study, we investigate the ancestry distribution in the T cell receptor sequencing(TCR-seq) studies to initial estimate the ancestry distribution in the open AIRR-seq studies. The result disclosed that 84.08% of the studies with reported ancestries are conducted under European ancestries, which omit other populational ancestries’ diversity in the open TCR-Seq studies.

scholarly journals The naive T-cell receptor repertoire has an extremely broad distribution of clone sizes

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Peter C de Greef ◽  
Theres Oakes ◽  
Bram Gerritsen ◽  
Mazlina Ismail ◽  
James M Heather ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Cell Repertoire ◽  
Clone Size ◽  
Receptor Repertoire ◽  
Tcr Repertoire ◽  
Naïve T Cell ◽  
Cell Receptor Repertoire ◽  
Naive T Cell

The clone size distribution of the human naive T-cell receptor (TCR) repertoire is an important determinant of adaptive immunity. We estimated the abundance of TCR sequences in samples of naive T cells from blood using an accurate quantitative sequencing protocol. We observe most TCR sequences only once, consistent with the enormous diversity of the repertoire. However, a substantial number of sequences were observed multiple times. We detect abundant TCR sequences even after exclusion of methodological confounders such as sort contamination, and multiple mRNA sampling from the same cell. By combining experimental data with predictions from models we describe two mechanisms contributing to TCR sequence abundance. TCRα abundant sequences can be primarily attributed to many identical recombination events in different cells, while abundant TCRβ sequences are primarily derived from large clones, which make up a small percentage of the naive repertoire, and could be established early in the development of the T-cell repertoire.

scholarly journals The naive T-cell receptor repertoire has an extremely broad distribution of clone sizes

2019 ◽  
Author(s):  
Peter C. de Greef ◽  
Theres Oakes ◽  
Bram Gerritsen ◽  
Mazlina Ismail ◽  
James M. Heather ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Computational Modelling ◽  
Cell Receptor ◽  
Sequencing Data ◽  
Receptor Repertoire ◽  
Cell Clones ◽  
Tcr Repertoire ◽  
Naïve T Cell ◽  
Naive T Cell

AbstractThe human naive T-cell receptor (TCR) repertoire is extremely diverse and accurately estimating its distribution is challenging. We address this challenge by combining a quantitative sequencing protocol of TCRA and TCRB sequences with computational modelling. We observed the vast majority of TCR chains only once in our samples, confirming the enormous diversity of the naive repertoire. However, a substantial number of sequences were observed multiple times within samples, and we demonstrated that this is due to expression by many cells in the naive pool. We reason that α and β chains are frequently observed due to a combination of selective processes and summation over multiple clones expressing these chains. We test the contribution of both mechanisms by predicting samples from phenomenological and mechanistically modelled repertoire distributions. By comparing these with sequencing data, we show that frequently observed chains are likely to be derived from multiple clones. Still, a neutral model of T-cell homeostasis cannot account for the observed distributions. We conclude that the data are only compatible with distributions of many small clones in combination with a sufficient number of very large naive T-cell clones, the latter most likely as a result of peripheral selection.

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