scholarly journals Predicting Cross-Reactivity and Antigen Specificity of T Cell Receptors

2020 ◽  
Vol 11 ◽  
Author(s):  
Chloe H. Lee ◽  
Mariolina Salio ◽  
Giorgio Napolitani ◽  
Graham Ogg ◽  
Alison Simmons ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptors ◽  
Cross Reactivity ◽  
Antigen Specificity ◽  
Cell Receptors

Recovery of Paired T Cell Receptors from Single-cell Seq-Well Libraries

2019 ◽  
Author(s):  
Ang A. Tu ◽  
Todd M. Gierahn ◽  
Brinda Monian ◽  
Duncan M. Morgan ◽  
Naveen K. Mehta ◽  
...  
Keyword(s):  
T Cells ◽  
Food Allergy ◽  
T Cell ◽  
Single Cell ◽  
T Cell Receptors ◽  
Immune Cell ◽  
Cost Effective ◽  
Antigen Specificity ◽  
Activated T Cells ◽  
Cell Receptors

Abstract High-throughput 3’ single-cell RNA-Sequencing (scRNA-Seq) allows for cost-effective, detailed characterization of thousands of individual immune cells from healthy and diseased tissues. Current techniques, however, are limited in their ability to elucidate essential immune cell features, including the variable sequences of T cell receptors (TCRs) that confer antigen specificity in T cells. Here, we present an enrichment strategy that enables simultaneous analysis of TCR variable sequences and corresponding full transcriptomes from 3’ barcoded scRNA-Seq samples. This approach is compatible with common 3’ scRNA-Seq methods, and adaptable to processed samples post hoc. We applied the technique to resolve clonotype-to-phenotype relationships among antigen-activated T cells from immunized mice and from patients with food allergy. We observed diverse but preferential cellular phenotypes manifest among subsets of expanded clonotypes, including functional Th2 states associated with food allergy. These results demonstrate the utility of our method when studying complex diseases in which clonotype-driven immune responses are critical to understanding the underlying biology.

scholarly journals T-cell Receptors Engineered De Novo for Peptide Specificity Can Mediate Optimal T-cell Activity without Self Cross-Reactivity

2019 ◽  
Vol 7 (12) ◽  
pp. 2025-2035 ◽  
Author(s):  
Preeti Sharma ◽  
Daniel T. Harris ◽  
Jennifer D. Stone ◽  
David M. Kranz
Keyword(s):  
T Cell ◽  
T Cell Receptors ◽  
De Novo ◽  
Cell Activity ◽  
Cross Reactivity ◽  
Cell Receptors ◽  
Peptide Specificity

scholarly journals Analysis of SARS-CoV-2 specific T-cell receptors in ImmuneCode reveals cross-reactivity to immunodominant Influenza M1 epitope

2020 ◽  
Author(s):  
John-William Sidhom ◽  
Alexander S. Baras
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
T Cell Receptors ◽  
Cell Receptor ◽  
Cross Reactivity ◽  
Cell Receptors

Adaptive Biotechnologies and Microsoft have recently partnered to release ImmuneCode, a database containing SARS-CoV-2 specific T-cell receptors derived through MIRA, a T-cell receptor (TCR) sequencing based sequencing approach to identify antigen-specific TCRs. Herein, we query the extent of cross reactivity between these derived SARS-CoV-2 specific TCRs and other known antigens present in McPas-TCR, a manually curated catalogue of pathology-associated TCRs. We reveal cross reactivity between SARS-CoV-2 specific TCRs and the immunodominant Influenza GILGFVFTL M1 epitope, suggesting the importance of further work in characterizing the implications of prior Influenza exposure or co-exposure to the pathology of SARS-CoV-2 illness.

scholarly journals TCR3d: The T cell receptor structural repertoire database

2019 ◽  
Vol 35 (24) ◽  
pp. 5323-5325 ◽  
Author(s):  
Ragul Gowthaman ◽  
Brian G Pierce
Keyword(s):  
T Cell ◽  
T Cell Receptors ◽  
Adaptive Immune System ◽  
Cell Receptor ◽  
Binding Mode ◽  
Computational Techniques ◽  
Antigen Specificity ◽  
Cell Receptors ◽  
Gene Usage ◽  
Mechanistic Basis

Abstract Summary T cell receptors (TCRs) are critical molecules of the adaptive immune system, capable of recognizing diverse antigens, including peptides, lipids and small molecules, and represent a rapidly growing class of therapeutics. Determining the structural and mechanistic basis of TCR targeting of antigens is a major challenge, as each individual has a vast and diverse repertoire of TCRs. Despite shared general recognition modes, diversity in TCR sequence and recognition represents a challenge to predictive modeling and computational techniques being developed to predict antigen specificity and mechanistic basis of TCR targeting. To this end, we have developed the TCR3d database, a resource containing all known TCR structures, with a particular focus on antigen recognition. TCR3d provides key information on antigen binding mode, interface features, loop sequences and germline gene usage. Users can interactively view TCR complex structures, search sequences of interest against known structures and sequences, and download curated datasets of structurally characterized TCR complexes. This database is updated on a weekly basis, and can serve the community as a centralized resource for those studying T cell receptors and their recognition. Availability and implementation The TCR3d database is available at https://tcr3d.ibbr.umd.edu/.

scholarly journals Structural Basis of Specificity and Cross-Reactivity in T Cell Receptors Specific for Cytochrome c–I-Ek

2011 ◽  
Vol 186 (10) ◽  
pp. 5823-5832 ◽  
Author(s):  
Evan W. Newell ◽  
Lauren K. Ely ◽  
Andrew C. Kruse ◽  
Philip A. Reay ◽  
Stephanie N. Rodriguez ◽  
...  
Keyword(s):  
T Cell ◽  
Cytochrome C ◽  
T Cell Receptors ◽  
Cross Reactivity ◽  
Structural Basis ◽  
Cell Receptors

scholarly journals Facile method for screening clinical T cell receptors for off-target peptide-HLA reactivity

2018 ◽  
Author(s):  
Marvin H. Gee ◽  
Xinbo Yang ◽  
K. Christopher Garcia
Keyword(s):  
T Cell ◽  
T Cell Receptors ◽  
Human Leukocyte ◽  
Cross Reactivity ◽  
Affinity Maturation ◽  
Yeast Display ◽  
Cell Therapies ◽  
Cell Receptors ◽  
Leukocyte Antigen ◽  
Clinical Toxicity

ABSTRACTT cell receptors (TCRs) exhibit varying degrees of cross-reactivity for peptides presented by the human leukocyte antigen (HLA). In engineered T cell therapies, TCR affinity maturation is a strategy to improve the sensitivity and potency to often a low-density peptide-HLA (pHLA) target. However, the process of affinity maturation towards a known pHLA complex can introduce new and untoward cross-reactivities that are difficult to detect and raises significant safety concerns. We developed a yeast-display platform of pHLA consisting of ~100 million different 9mer peptides presented by HLA-A*01 and used a previously established selection approach to validate the specificity and cross-reactivity of the A3A TCR, an affinity-matured TCR against the MAGE-A3 target (EVDPIGHLY). We were able to identify reactivity against the titin peptide (ESDPIVAQY), to which there is now known clinical toxicity. We propose the use of yeast-display of pHLA libraries to determine cross-reactive profiles of candidate clinical TCRs to ensure safety and pHLA specificity of natural and affinity-matured TCRs.

scholarly journals SARS-CoV-2 epitopes are recognized by a public and diverse repertoire of human T-cell receptors

2020 ◽  
Author(s):  
Alina S. Shomuradova ◽  
Murad S. Vagida ◽  
Savely A. Sheetikov ◽  
Ksenia V. Zornikova ◽  
Dmitry Kiryukhin ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptors ◽  
Cell Response ◽  
Adaptive Immune Response ◽  
Cross Reactivity ◽  
T Cell Response ◽  
Cell Reactivity ◽  
Cell Receptors ◽  
Human T Cell ◽  
Healthy Donors

SummaryUnderstanding the hallmarks of the adaptive immune response to SARS-CoV-2 is critical for fighting the COVID-19 pandemic. We assessed the antibody and T-cell reactivity in COVID-19 convalescent patients and healthy donors sampled both prior to and during the pandemic. The numbers of SARS-CoV-2-specific T cells were increased in healthy donors examined during COVID-19. Combined with the absence of symptoms and humoral response across that group, this finding suggests that some individuals might be protected by T-cell cross-reactivity. In convalescent patients we observed public and diverse T-cell response to SARS-CoV-2 epitopes, revealing T-cell receptor motifs with germline-encoded features. Bulk CD4+ and CD8+ T-cell responses to Spike glycoprotein were mediated by groups of homologous T-cell receptors, some of them shared across multiple donors. Overall, our results demonstrate that T-cell response to SARS-CoV-2, including the identified set of specific T-cell receptors, can serve as a useful biomarker for surveying viral exposure and immunity.

scholarly journals Identification of Cross-Reactive CD8+ T Cell Receptors with High Functional Avidity to a SARS-CoV-2 Immunodominant Epitope and Its Natural Mutant Variants

2020 ◽  
Author(s):  
Chao Hu ◽  
Meiying Shen ◽  
Xiaojian Han ◽  
Qian Chen ◽  
Luo Li ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptors ◽  
Vaccine Development ◽  
Ex Vivo ◽  
T Cell Responses ◽  
Cross Reactivity ◽  
Functional Avidity ◽  
Cell Receptors ◽  
Cell Functions ◽  
Cell Responses

ABSTRACTDespite the growing knowledge of T cell responses and their epitopes in COVID-19 patients, there is a lack of detailed characterizations for T cell-antigen interactions and T cell functions. Using a peptide library predicted with HLA class I-restriction, specific CD8+ T cell responses were identified in over 75% of COVID-19 convalescent patients. Among the 15 SARS-CoV-2 epitopes identified from the S and N proteins, N361-369 (KTFPPTEPK) was the most dominant epitope. Importantly, we discovered 2 N361-369-specific T cell receptors (TCRs) with high functional avidity, and they exhibited complementary cross-reactivity to reported N361-369 mutant variants. In dendritic cells (DCs) and the lung organoid model, we found that the N361-369 epitope could be processed and endogenously presented to elicit the activation and cytotoxicity of CD8+ T cells ex vivo. Our study evidenced potential mechanisms of cellular immunity to SARS-CoV-2, illuminating natural ways of viral clearance with high relevancy in the vaccine development.

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