scholarly journals Junctional diversity in signal joints from T cell receptor beta and delta loci via terminal deoxynucleotidyl transferase and exonucleolytic activity.

1996 ◽  
Vol 184 (5) ◽  
pp. 1919-1926 ◽  
Author(s):  
S Candéias ◽  
K Muegge ◽  
S K Durum
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Recombination Reaction ◽  
Variable Regions ◽  
Tcr Repertoire ◽  
Repertoire Diversity ◽  
T Cell Receptor Beta ◽  
Junctional Diversity

The site-specific V(D)J recombination reaction necessary to assemble the genes coding for immunoglobulin (Ig) and T cell receptor (TCR) variable regions is initiated by a precise double strand cut at the border of the recombination signals flanking the genes. Extensive processing of the coding ends before their ligation accounts for most of the Ig and TCR repertoire diversity. This processing includes both base additions to and loss from the coding ends. On the other hand, it has generally been thought that signal ends are not modified before they are fused, and that signal joints consist of a perfect head-to-head ligation of the recombination signals. In this study, we analyzed signal joints created during the rearrangement of different TCR-beta and TCR-delta genes in thymocytes. We show that a significant fraction (up to 24%) of these signal joints exhibits junctional diversity. This diversity results from N nucleotide additions for TCR-beta signal joints, and from N additions and exonucleolytic digestion for TCR-delta joints. Altogether, our findings suggest that: (a) signal ends can undergo some of the same modifications as coding ends, (b) inversional rearrangement generates more diversity than deletional events, and (c) fine differences exist in the recombinase/DNA complexes formed at each rearranging locus.

scholarly journals Systematic profiling of full-length immunoglobulin and T-cell receptor repertoire diversity in rhesus macaque through long read transcriptome sequencing

2019 ◽  
Author(s):  
Hayden N. Brochu ◽  
Elizabeth Tseng ◽  
Elise Smith ◽  
Matthew J. Thomas ◽  
Aiden Jones ◽  
...  
Keyword(s):  
T Cell ◽  
Rhesus Macaque ◽  
T Cell Receptor ◽  
Focal Point ◽  
Cell Receptor ◽  
Full Length ◽  
Variable Regions ◽  
Tcr Repertoire ◽  
Long Read ◽  
Repertoire Diversity

AbstractThe diversity of immunoglobulin (Ig) and T-cell receptor (TCR) repertoires is a focal point of immunological studies. Rhesus macaques are key for modeling human immune responses, placing critical importance on the accurate annotation and quantification of their Ig and TCR repertoires. However, due to incomplete reference resources, the coverage and accuracy of the traditional targeted amplification strategies for profiling rhesus Ig and TCR repertoires are largely unknown. Here, using long read sequencing, we sequenced four Indian-origin rhesus macaque tissues and obtained high quality, full-length sequences for over 6,000 unique Ig and TCR transcripts, without the need for sequence assembly. We constructed the first complete reference set for the constant regions of all known isotypes and chain types of rhesus Ig and TCR repertoires. We show that sequence diversity exists across the entire variable regions of rhesus Ig and TCR transcripts. Consequently, existing strategies using targeted amplification of rearranged variable regions comprised of V(D)J gene segments miss a significant fraction (27% to 53% and 42% to 49%) of rhesus Ig/TCR diversity. To overcome these limitations, we designed new rhesus-specific assays that remove the need for primers conventionally targeting variable regions and allow single cell-level Ig and TCR repertoire analysis. Our improved approach will enable future studies to fully capture rhesus Ig and TCR repertoire diversity and is applicable for improving annotations in any model organism.

scholarly journals Terminal deoxynucleotidyl transferase expression can precede T cell receptor beta chain and gamma chain rearrangement in T cell acute lymphoblastic leukemia

Blood ◽  
1987 ◽  
Vol 69 (1) ◽  
pp. 356-360
Author(s):  
JM Greenberg ◽  
JH Kersey
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
T Cell Receptor ◽  
Lymphoblastic Leukemia ◽  
Cell Receptor ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Beta Chain ◽  
Gamma Chain ◽  
T Cell Receptor Beta ◽  
Receptor Beta

The nuclear enzyme terminal deoxynucleotidyl transferase (TdT) is thought to contribute to the diversity of certain immunoglobulin and T cell receptor gene rearrangements through the addition of random nucleotides at their variable (V)-joining (J) region junctions. An acute lymphoblastic leukemia (ALL) with an immature T cell phenotype (CD7+, CD5+, CD1+/-, CD2+/-, CD3-, CD4-, CD8-) was found to be TdT+ with germline immunoglobulin heavy chain, T cell receptor beta chain, and T cell gamma chain genes. The data indicate that TdT expression can precede T gamma and T beta rearrangement during T lymphoid ontogeny consistent with its proposed association with the T cell receptor rearrangement process. Southern analysis of certain cases of T-ALL may not result in the detection of a monoclonal population of cells.

scholarly journals Terminal deoxynucleotidyl transferase expression can precede T cell receptor beta chain and gamma chain rearrangement in T cell acute lymphoblastic leukemia

Blood ◽  
1987 ◽  
Vol 69 (1) ◽  
pp. 356-360 ◽  
Author(s):  
JM Greenberg ◽  
JH Kersey
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
T Cell Receptor ◽  
Lymphoblastic Leukemia ◽  
Cell Receptor ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Beta Chain ◽  
Gamma Chain ◽  
T Cell Receptor Beta ◽  
Receptor Beta

Abstract The nuclear enzyme terminal deoxynucleotidyl transferase (TdT) is thought to contribute to the diversity of certain immunoglobulin and T cell receptor gene rearrangements through the addition of random nucleotides at their variable (V)-joining (J) region junctions. An acute lymphoblastic leukemia (ALL) with an immature T cell phenotype (CD7+, CD5+, CD1+/-, CD2+/-, CD3-, CD4-, CD8-) was found to be TdT+ with germline immunoglobulin heavy chain, T cell receptor beta chain, and T cell gamma chain genes. The data indicate that TdT expression can precede T gamma and T beta rearrangement during T lymphoid ontogeny consistent with its proposed association with the T cell receptor rearrangement process. Southern analysis of certain cases of T-ALL may not result in the detection of a monoclonal population of cells.

Reduction Of Immune Repertoire Diversity Through DNA Sequence Constraints At VDJ Junctions

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4944-4944
Author(s):  
Bryan Howie ◽  
Harlan Robins ◽  
Christopher S Carlson
Keyword(s):  
Immune System ◽  
T Cell ◽  
T Cell Receptor ◽  
Adaptive Immune System ◽  
Cell Receptor ◽  
Immune Repertoire ◽  
Adaptive Immune ◽  
Repertoire Diversity ◽  
Equity Ownership ◽  
Junctional Diversity

Abstract B and T lymphocytes are effector cells of the adaptive immune system. These cells express surface receptors that bind a huge variety of antigens, and together they comprise a person’s immune repertoire. A diverse repertoire is essential for mounting robust immune responses against a wide range of pathogens, and repertoire diversity affects the probability that DNA sequencing can uniquely tag a clonally expanded population of cells for the detection of minimum residual disease (MRD) during cancer treatment. Immune repertoire diversity arises partly through the combinatorial splicing of gene segments from the variable (V), diversity (D), and joining (J) regions of a B or T cell receptor locus. Much additional diversity is created through the stochastic insertion and deletion of nucleotides at the splice junctions, and by somatic hypermutation (SHM) in maturing lymphocytes. The generation of junctional diversity is an important part of this process, but it may be constrained by the underlying biological mechanisms. To explore the landscape of junctional diversity among immune receptor loci, we developed a likelihood model that can annotate VDJ junctions in the presence of SHM and compute the probability that a given receptor sequence was generated only once in a person’s repertoire, which is essential for tracking MRD. Using high-throughput sequencing data from several individuals and a range of receptor loci, we identify mechanistic constraints that limit B and T cell receptor diversity. For example, we show that the usual variability in CDR3 length is reduced at the immunoglobulin kappa (IgK) locus, and we connect this finding to sequence motifs that constrain nucleotide deletion at the ends of IgK gene segments. Our findings will inform future genetic studies of the adaptive immune system, and they provide quantitative guidance for deciding which cancer clones can be tracked for reliable MRD detection. Disclosures: Howie: Adaptive Biotechnologies: Employment, Equity Ownership. Robins:Adaptive Biotechnologies: Consultancy, Equity Ownership, Patents & Royalties. Carlson:Adaptive Biotechnologies: Consultancy, Equity Ownership, Patents & Royalties.

scholarly journals Characterization of T-Cell Receptor Repertoire in Patients with Rheumatoid Arthritis Receiving Biologic Therapies

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Che-Mai Chang ◽  
Yu-Wen Hsu ◽  
Henry Sung-Ching Wong ◽  
James Cheng-Chung Wei ◽  
Xiao Liu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cell ◽  
Disease Activity ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Therapeutic Effects ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Tcr Repertoire ◽  
Repertoire Diversity

Rheumatoid arthritis (RA) is a systematic autoimmune disease, predominantly causing chronic polyarticular inflammation and joint injury of patients. For the treatment of RA, biologic disease-modifying antirheumatic drugs (bDMARDs) have been used to reduce inflammation and to interfere with disease progression through targeting and mediating the immune system. Although the therapeutic effects of bDMARDs in RA patients have been widely reported, whether these drugs also play important roles in T-cell repertoire status is still unclear. We therefore designed the study to identify the role of T-cell repertoire profiles in RA patients with different types of bDMARD treatments. A high-throughput sequencing approach was applied to profile the T-cell receptor beta chain (TCRB) repertoire of circulating T lymphocytes in eight patients given adalimumab (anti-TNF-α) with/without the following use of either rituximab (anti-CD20) or tocilizumab (anti-IL6R). We subsequently analyzed discrepancies in the clonal diversity and CDR3 length distribution as well as usages of the V and J genes of TCRB repertoire and interrogated the association between repertoire diversity and disease activities followed by the treatment of bDMARDs in these RA patients. All groups of patients showed well-controlled DAS28 scores (<2.6) after different treatment regimens of drugs and displayed no significant statistical differences in repertoire diversity, distribution of CDR3 lengths, and usage of V and J genes of TCRB. Nonetheless, a trend between overall TCRB repertoire diversity and disease activity scores in all bDMARD-treated RA patients was observed. Additionally, age was found to be associated with repertoire diversity in RA patients treated with bDMARDs. Through the profiling of the TCR repertoire in RA patients receiving different biologic medications, our study indicated an inverse tendency between TCR repertoire diversity and disease activity after biologic treatment in RA patients.

scholarly journals Rearrangements of immunoglobulin and T cell receptor beta and gamma genes are associated with terminal deoxynucleotidyl transferase expression in acute myeloid leukemia.

1987 ◽  
Vol 165 (3) ◽  
pp. 879-890 ◽  
Author(s):  
R Foa ◽  
G Casorati ◽  
M C Giubellino ◽  
G Basso ◽  
R Schirò ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Gene Rearrangement ◽  
Cell Lineage ◽  
Cell Receptor ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Chain Gene ◽  
T Cell Receptor Beta ◽  
Receptor Beta ◽  
Acute Myeloid

The cell origin of the rare terminal deoxynucleotidyl transferase (TdT)-positive acute myeloid leukemias (AML) was investigated at the molecular level, by examining the configuration of the Ig H (Igh) and L (Ig kappa, Ig lambda) chain gene regions, and of the T cell receptor (TCR) beta and T cell rearranging (TRG) gamma loci. In 8 of the 10 TdT+ AML analyzed (classified as myeloid according to morphological and cytochemical criteria, and to the reactivity with one or more antimyeloid mAbs), a rearrangement of the Igh chain gene was found. In TdT- AML, evidence of an Igh gene reorganization was instead observed only in 2 of the 42 patients studied. Furthermore, evidence of TCR-beta and/or TRG-gamma gene rearrangement was observed in four AML, all of which belonged to the Igh-rearranged TdT+ group. In three cases (one TdT+ and two TdT-), the Ig kappa L chain gene was also in a rearranged position. These findings demonstrate a highly significant correlation between TdT expression and DNA rearrangements at the Igh and TCR chain gene regions and support the view that this enzyme plays an important role in the V-(D)-J recombination machinery. Overall, the genomic configuration, i.e., JH gene rearrangement sometimes coupled to a kappa L chain and TCR gene reorganization, similar to that found in non-T-ALL, suggests that in most cases of TdT+ AML, the neoplastic clone, despite the expression of myeloid-related features, is characterized by cells molecularly committed along the B cell lineage.

scholarly journals Blood T-cell receptor diversity decreases during the course of HIV infection, but the potential for a diverse repertoire persists

Blood ◽  
2012 ◽  
Vol 119 (15) ◽  
pp. 3469-3477 ◽  
Author(s):  
Paul D. Baum ◽  
Jennifer J. Young ◽  
Diane Schmidt ◽  
Qianjun Zhang ◽  
Rebecca Hoh ◽  
...  
Keyword(s):  
T Cell ◽  
Hiv Infection ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Cd4 T Cell ◽  
Tcr Repertoire ◽  
Repertoire Diversity ◽  
Tcr Diversity ◽  
Cell Subpopulations ◽  
T Cell Subpopulations

HIV infection results in a decrease in circulating CD4+ T-cell and naive T-cell numbers. If such losses were associated with an erosion of T-cell receptor (TCR) repertoire diversity in the peripheral T-cell pool, this might exacerbate the state of persistent immunodeficiency. Existing methods for the analysis of the TCR repertoire have demonstrated skewed distributions of TCR genes in HIV-infected subjects but cannot directly measure TCR diversity. Here we used AmpliCot, a quantitative assay based on DNA hybridization kinetics, to measure TCR diversity in a cross-sectional comparison of 19 HIV-infected persons to 18 HIV-uninfected controls. HIV-infected persons had a 10-fold decrease in total TCR repertoire diversity in 1.5 mL of blood compared with uninfected controls, with decreased diversity correlating most closely with a lower CD4+ T-cell percentage. Nonetheless, the TCR repertoire diversity of sort-purified T-cell subpopulations in HIV-infected and HIV-uninfected subjects was comparable. These observations suggest that the TCR repertoire diversity changes in whole blood during HIV disease progression are primarily the result of changes in the number and proportion of T-cell subpopulations and that most HIV-infected persons may retain a sufficiently diverse TCR repertoire to permit immune reconstitution with antiretroviral therapy alone, without thymopoiesis.

scholarly journals T Cell Receptor Beta (TRB) Germline Variability is Revealed by Inference From Repertoire Data

2021 ◽  
Author(s):  
Aviv Omer ◽  
Ayelet Peres ◽  
Oscar L Rodrigues ◽  
Corey T Watson ◽  
William Lees ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
T Cell Receptor ◽  
Clinical Importance ◽  
Variable Region ◽  
Cell Receptor ◽  
Genomic Variation ◽  
Variable Regions ◽  
T Cell Receptor Beta ◽  
Receptor Beta

T and B cell repertoires constitute the foundation of adaptive immunity. Adaptive immune receptor repertoire sequencing (AIRR-seq) is a common approach to study immune system dynamics. Understanding the genetic factors influencing the composition and dynamics of these repertoires is of major scientific and clinical importance. The chromosomal loci encoding for the variable regions of T and B cell receptors (TCRs and BCRs, respectively) are challenging to decipher due to repetitive elements and undocumented structural variants. To confront this challenge, AIRR-seq-based methods have been developed recently for B cells, enabling genotype and haplotype inference and discovery of undocumented alleles. Applying these methods to AIRR-seq data reveals a plethora of undocumented genomic variations. However, this approach relies on complete coverage of the receptors' variable regions, and most T cell studies sequence only a small fraction of the variable region. Here, we adapted BCR inference methods to full and partial TCR sequences, and identified 38 undocumented polymorphisms in TRBV, 15 of them were also observed in genomic data assemblies. Further, we identified 31 undocumented 5' UTR sequences. A subset of these inferences was also observed using independent genomic approaches. We found the two documented TRBD2 alleles to be equally abundant in the population, and show that the single nucleotide that differentiates them is strongly associated with dramatic changes in the expressed repertoire. Our findings expand the knowledge of genomic variation in the TRB (T Cell Receptor Beta) locus and provide a basis for annotation of TCR repertoires for future basic and clinical studies.

scholarly journals A method for producing monoclonal antibodies to human T-cell-receptor beta-chain variable regions.

1993 ◽  
Vol 90 (22) ◽  
pp. 10454-10458 ◽  
Author(s):  
M. F. Callan ◽  
H. T. Reyburn ◽  
P. Bowness ◽  
T. H. Ottenhoff ◽  
I. Engel ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Beta Chain ◽  
Variable Regions ◽  
Human T Cell ◽  
T Cell Receptor Beta ◽  
Receptor Beta

scholarly journals Human γδ TCR Repertoires in Health and Disease

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 800 ◽  
Author(s):  
Alina Suzann Fichtner ◽  
Sarina Ravens ◽  
Immo Prinz
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Γδ T Cells ◽  
Cell Receptor ◽  
Γδ T Cell ◽  
Tcr Repertoire ◽  
Repertoire Diversity ◽  
Health And Disease ◽  
Αβ T Cells

The T cell receptor (TCR) repertoires of γδ T cells are very different to those of αβ T cells. While the theoretical TCR repertoire diversity of γδ T cells is estimated to exceed the diversity of αβ T cells by far, γδ T cells are still understood as more invariant T cells that only use a limited set of γδ TCRs. Most of our current knowledge of human γδ T cell receptor diversity builds on specific monoclonal antibodies that discriminate between the two major subsets, namely Vδ2+ and Vδ1+ T cells. Of those two subsets, Vδ2+ T cells seem to better fit into a role of innate T cells with semi-invariant TCR usage, as compared to an adaptive-like biology of some Vδ1+ subsets. Yet, this distinction into innate-like Vδ2+ and adaptive-like Vδ1+ γδ T cells does not quite recapitulate the full diversity of γδ T cell subsets, ligands and interaction modes. Here, we review how the recent introduction of high-throughput TCR repertoire sequencing has boosted our knowledge of γδ T cell repertoire diversity beyond Vδ2+ and Vδ1+ T cells. We discuss the current understanding of clonal composition and the dynamics of human γδ TCR repertoires in health and disease.

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