scholarly journals Deep learning identifies antigenic determinants of severe SARS-CoV-2 infection within T-cell repertoires

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
John-William Sidhom ◽  
Alexander S. Baras
Keyword(s):  
Deep Learning ◽  
T Cell ◽  
Clinical Outcomes ◽  
Clinical Course ◽  
Severity Of Illness ◽  
Severe Infection ◽  
Cell Receptor ◽  
Asymptomatic Infection ◽  
Antigenic Determinants ◽  
Repertoire Sequencing

AbstractSARS-CoV-2 infection is characterized by a highly variable clinical course with patients experiencing asymptomatic infection all the way to requiring critical care support. This variation in clinical course has led physicians and scientists to study factors that may predispose certain individuals to more severe clinical presentations in hopes of either identifying these individuals early in their illness or improving their medical management. We sought to understand immunogenomic differences that may result in varied clinical outcomes through analysis of T-cell receptor sequencing (TCR-Seq) data in the open access ImmuneCODE database. We identified two cohorts within the database that had clinical outcomes data reflecting severity of illness and utilized DeepTCR, a multiple-instance deep learning repertoire classifier, to predict patients with severe SARS-CoV-2 infection from their repertoire sequencing. We demonstrate that patients with severe infection have repertoires with higher T-cell responses associated with SARS-CoV-2 epitopes and identify the epitopes that result in these responses. Our results provide evidence that the highly variable clinical course seen in SARS-CoV-2 infection is associated to certain antigen-specific responses.

scholarly journals Human T cell receptor occurrence patterns encode immune history, genetic background, and receptor specificity

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
William S DeWitt ◽  
Anajane Smith ◽  
Gary Schoch ◽  
John A Hansen ◽  
Frederick A Matsen ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Genetic Background ◽  
Cell Receptor ◽  
Sequencing Data ◽  
Human T Cell ◽  
Disease Associations ◽  
Repertoire Sequencing ◽  
Mhc Polymorphism ◽  
Occurrence Patterns

The T cell receptor (TCR) repertoire encodes immune exposure history through the dynamic formation of immunological memory. Statistical analysis of repertoire sequencing data has the potential to decode disease associations from large cohorts with measured phenotypes. However, the repertoire perturbation induced by a given immunological challenge is conditioned on genetic background via major histocompatibility complex (MHC) polymorphism. We explore associations between MHC alleles, immune exposures, and shared TCRs in a large human cohort. Using a previously published repertoire sequencing dataset augmented with high-resolution MHC genotyping, our analysis reveals rich structure: striking imprints of common pathogens, clusters of co-occurring TCRs that may represent markers of shared immune exposures, and substantial variations in TCR-MHC association strength across MHC loci. Guided by atomic contacts in solved TCR:peptide-MHC structures, we identify sequence covariation between TCR and MHC. These insights and our analysis framework lay the groundwork for further explorations into TCR diversity.

scholarly journals Peripheral T cell receptor diversity is associated with clinical outcomes following ipilimumab treatment in metastatic melanoma

2015 ◽  
Vol 3 (1) ◽  
Author(s):  
Michael A. Postow ◽  
Manuarii Manuel ◽  
Phillip Wong ◽  
Jianda Yuan ◽  
Zhiwan Dong ◽  
...  
Keyword(s):  
T Cell ◽  
Metastatic Melanoma ◽  
Clinical Outcomes ◽  
T Cell Receptor ◽  
Cell Receptor

scholarly journals Expression of T cell receptor genes in an antigen-specific hybridoma and radiation-induced variants.

1986 ◽  
Vol 164 (1) ◽  
pp. 113-130 ◽  
Author(s):  
N R Gascoigne ◽  
S Waters ◽  
J F Elliott ◽  
C Victor-Kobrin ◽  
C Goodnow ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Antigenic Determinants ◽  
Beta Chain ◽  
Stable Production ◽  
Radiation Induced ◽  
V Region ◽  
Beta Chain Genes ◽  
Antigen Reactivity

We have analyzed a series of mutants derived from a KLH-specific, I-E-restricted T hybridoma (FN1-18) which have lost antigen-reactivity while retaining both T cell receptor idiotypic determinants and the ability to respond to Con A. The variants have not gained any detectable alloreactivity, nor is there an obvious lesion in the mutants' beta chain DNA containing the utilized beta chain genes. This loss of antigen reactivity is due to a failure of stable production of the specific V beta-containing mRNA. Our results indicate that in FN1-18, the T cell receptor antigenic determinants are most likely carried by the alpha chain alone or by a complementation product of the V alpha FN1-18 with the V beta of BW5147. V beta FN1-18 represents a previously undescribed T cell receptor V region.

scholarly journals Convergent selection in antibody repertoires is revealed by deep learning

2020 ◽  
Author(s):  
Simon Friedensohn ◽  
Daniel Neumeier ◽  
Tarik A Khan ◽  
Lucia Csepregi ◽  
Cristina Parola ◽  
...  
Keyword(s):  
Deep Learning ◽  
T Cell ◽  
B Cell ◽  
Recombinant Expression ◽  
Cell Receptor ◽  
Support Vector ◽  
Cell Receptors ◽  
Sequence Patterns ◽  
Antibody Repertoires ◽  
Selection Of

SUMMARYAdaptive immunity is driven by the ability of lymphocytes to undergo V(D)J recombination and generate a highly diverse set of immune receptors (B cell receptors/secreted antibodies and T cell receptors) and their subsequent clonal selection and expansion upon molecular recognition of foreign antigens. These principles lead to remarkable, unique and dynamic immune receptor repertoires1. Deep sequencing provides increasing evidence for the presence of commonly shared (convergent) receptors across individual organisms within one species2-4. Convergent selection of specific receptors towards various antigens offers one explanation for these findings. For example, single cases of convergence have been reported in antibody repertoires of viral infection or allergy5-8. Recent studies demonstrate that convergent selection of sequence motifs within T cell receptor (TCR) repertoires can be identified on an even wider scale9,10. Here we report that there is extensive convergent selection in antibody repertoires of mice for a range of protein antigens and immunization conditions. We employed a deep learning approach utilizing variational autoencoders (VAEs) to model the underlying process of B cell receptor (BCR) recombination and assume that the data generation follows a Gaussian mixture model (GMM) in latent space. This provides both a latent embedding and cluster labels that group similar sequences, thus enabling the discovery of a multitude of convergent, antigen-associated sequence patterns. Using a linear, one-versus-all support vector machine (SVM), we confirm that the identified sequence patterns are predictive of antigenic exposure and outperform predictions based on the occurrence of public clones. Recombinant expression of both natural and in silico-generated antibodies possessing convergent patterns confirms their binding specificity to target antigens. Our work highlights to which extent convergence in antibody repertoires can occur and shows how deep learning can be applied for immunodiagnostics and antibody discovery and engineering.

scholarly journals PDCT-12. TRACKING T-CELL IMMUNE RECONSTITUTION AFTER ADOPTIVE CELLULAR THERAPY TARGETING RECURRENT MEDULLOBLASTOMA AND PNETS USING DEEP T-CELL RECEPTOR (TCR) REPERTOIRE SEQUENCING

2017 ◽  
Vol 19 (suppl_6) ◽  
pp. vi186-vi186
Author(s):  
Oleg Yegorov ◽  
Yanina Yegorova ◽  
Anjelika Dechkovskaia ◽  
Jianping Huang ◽  
Sridharan Gururangan ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Immune Reconstitution ◽  
Cellular Therapy ◽  
Cell Receptor ◽  
Adoptive Cellular Therapy ◽  
Tcr Repertoire ◽  
Repertoire Sequencing

scholarly journals Ultra-Efficient Short Read Sequencing of T Cell Receptor Repertoires

2018 ◽  
Author(s):  
Janelle M. Montagne ◽  
Xuwen Alice Zheng ◽  
Iago Pinal-Fernandez ◽  
Jose C. Milisenda ◽  
Lisa Christopher-Stine ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Large Scale ◽  
Cell Receptor ◽  
Short Read ◽  
Industry Standards ◽  
Tcr Repertoire ◽  
Sporadic Inclusion Body Myositis ◽  
Repertoire Sequencing ◽  
Primer Sets

Abstract:T cell receptor (TCR) repertoire sequencing is increasingly employed to characterize adaptive immune responses. However, current TCR sequencing methodologies are complex and expensive, limiting the scale of feasible studies. Here we present Framework Region 3 AmplifiKation sequencing (FR3AK-seq), a simplified multiplex PCR-based approach for the ultra-efficient analysis of TCR complementarity determining region 3 (CDR3) repertoires. By using minimal primer sets targeting a conserved region adjacent to CDR3, undistorted amplicons are analyzed via short read, single-end sequencing. We find that FR3AK-seq is sensitive and quantitative, performing comparably to two industry standards. FR3AK-seq was utilized to quickly and inexpensively characterize the T cell infiltrates of muscle biopsies obtained from 145 patients with idiopathic inflammatory myopathies and controls. A cluster of related TCRs was identified in samples from patients with sporadic inclusion body myositis, suggesting the presence of a shared antigen-driven response. The ease and minimal cost of FR3AK-seq removes critical barriers to routine, large-scale TCR CDR3 repertoire analyses.

scholarly journals Optimization of T Cell Redirecting Strategies: Obtaining Inspirations From Natural Process of T Cell Activation

2021 ◽  
Vol 12 ◽  
Author(s):  
Yiyuan Gao ◽  
Yuedi Wang ◽  
Feifei Luo ◽  
Yiwei Chu
Keyword(s):  
T Cells ◽  
T Cell ◽  
Clinical Outcomes ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immunological Synapse ◽  
Cell Receptor ◽  
T Cell Response ◽  
Antigen Receptors ◽  
Cell Therapies

Chimeric antigen receptors (CARs) or bispecific antibodies (bsAbs) redirected T cell against tumors is one of the most promising immunotherapy approaches. However, insufficient clinical outcomes are still observed in treatments of both solid and non-solid tumors. Limited efficacy and poor persistence are two major challenges in redirected T cell therapies. The immunological synapse (IS) is a vital component during the T cell response, which largely determines the clinical outcomes of T cell-based therapies. Here, we review the structural and signaling characteristics of IS formed by natural T cells and redirected T cells. Furthermore, inspired by the elaborate natural T cell receptor-mediated IS, we provide potential strategies for higher efficacy and longer persistence of redirected T cells.

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