A Reliable and Safe T Cell Repertoire based on Low-affinity T Cell Receptors

2001 ◽  
Vol 209 (4) ◽  
pp. 465-486 ◽  
Author(s):  
H.A. VAN DEN BERG ◽  
D.A. RAND ◽  
N.J. BURROUGHS
Keyword(s):  
T Cell ◽  
T Cell Receptors ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Cell Receptors

scholarly journals CD1b tetramers bind αβ T cell receptors to identify a mycobacterial glycolipid-reactive T cell repertoire in humans

2011 ◽  
Vol 208 (9) ◽  
pp. 1741-1747 ◽  
Author(s):  
Anne G. Kasmar ◽  
Ildiko van Rhijn ◽  
Tan-Yun Cheng ◽  
Marie Turner ◽  
Chetan Seshadri ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptors ◽  
Direct Detection ◽  
Ex Vivo ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Cell Receptors ◽  
Cell Staining ◽  
Antigen Presenting

Microbial lipids activate T cells by binding directly to CD1 and T cell receptors (TCRs) or by indirect effects on antigen-presenting cells involving induction of lipid autoantigens, CD1 transcription, or cytokine release. To distinguish among direct and indirect mechanisms, we developed fluorescent human CD1b tetramers and measured T cell staining. CD1b tetramer staining of T cells requires glucose monomycolate (GMM) antigens, is specific for TCR structure, and is blocked by a recombinant clonotypic TCR comprised of TRAV17 and TRBV4-1, proving that CD1b–glycolipid complexes bind the TCR. GMM-loaded tetramers brightly stain a small subpopulation of blood-derived cells from humans infected with Mycobacterium tuberculosis, providing direct detection of a CD1b-reactive T cell repertoire. Polyclonal T cells from patients sorted with tetramers are activated by GMM antigens presented by CD1b. Whereas prior studies emphasized CD8+ and CD4−CD8− CD1b-restricted clones, CD1b tetramer-based studies show that nearly all cells express the CD4 co-receptor. These findings prove a cognate mechanism whereby CD1b–glycolipid complexes bind to TCRs. CD1b tetramers detect a natural CD1b-restricted T cell repertoire ex vivo with unexpected features, opening a new investigative path to study the human CD1 system.

Aging-related changes in human T-cell repertoire over 20 years delineated by deep sequencing of peripheral T-cell receptors

2017 ◽  
Vol 96 ◽  
pp. 29-37 ◽  
Author(s):  
Kengo Yoshida ◽  
John B. Cologne ◽  
Kismet Cordova ◽  
Munechika Misumi ◽  
Mika Yamaoka ◽  
...  
Keyword(s):  
T Cell ◽  
Deep Sequencing ◽  
T Cell Receptors ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Cell Receptors ◽  
Human T Cell

scholarly journals Isolation of human MHC class II-restricted T cell receptors from the autologous T-cell repertoire with potent anti-leukaemic reactivity

Immunology ◽  
2012 ◽  
Vol 137 (3) ◽  
pp. 226-238 ◽  
Author(s):  
Luise U Weigand ◽  
Xiaoling Liang ◽  
Sabine Schmied ◽  
Sabine Mall ◽  
Richard Klar ◽  
...  
Keyword(s):  
T Cell ◽  
Mhc Class Ii ◽  
T Cell Receptors ◽  
Class Ii ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Cell Receptors

scholarly journals The V beta 17+ T cell repertoire: skewed J beta usage after thymic selection; dissimilar CDR3s in CD4+ versus CD8+ cells.

1991 ◽  
Vol 174 (5) ◽  
pp. 989-1000 ◽  
Author(s):  
S Candéias ◽  
C Waltzinger ◽  
C Benoist ◽  
D Mathis
Keyword(s):  
T Cell ◽  
T Cell Receptors ◽  
Gene Rearrangement ◽  
Variable Region ◽  
Thymic Selection ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Cd8 Cells ◽  
Molecular Events ◽  
Peripheral T Cells

To ascertain how the actual repertoire of T cell receptors (TCRs) deviates from the theoretical, we have generated a large number of junctional region sequences from TCRs carrying the V beta 17 variable region. The greater than 600 sequences analyzed represent transcripts from nine different cell populations, permitting several comparisons: transcripts from an expressed vs. a non-expressed V beta 17 allele, those from E+ vs. E- mice, transcripts from immature vs. mature thymocytes, those from thymic vs. peripheral T cells, and those from CD4+ vs. CD8+ cells. These comparisons have allowed us to distinguish between the influence of molecular events involved in TCR gene rearrangement and that of various selection events that shape the T cell repertoire. Our most striking findings are: (a) that J beta usage is markedly skewed, partly due to recombination mechanics and partly due to selection forces: in particular, those mediated by the class II E molecule in the thymus; and (b) that TCRs on CD4+ and CD8+ cells show intriguing dissimilarities. In addition, we present evidence that N nucleotide additions occur with clear biases, probably due to idiosyncrasies of the recombination enzymes, and provide arguments that TCR and immunoglobulin CDR3s have distinct structures.

scholarly journals De novo prediction of cancer-associated T cell receptors for noninvasive cancer detection

2020 ◽  
Vol 12 (557) ◽  
pp. eaaz3738 ◽  
Author(s):  
Daria Beshnova ◽  
Jianfeng Ye ◽  
Oreoluwa Onabolu ◽  
Benjamin Moon ◽  
Wenxin Zheng ◽  
...  
Keyword(s):  
T Cell ◽  
Cancer Detection ◽  
T Cell Receptors ◽  
Tumor Antigens ◽  
De Novo ◽  
Early Stage ◽  
Area Under The Curve ◽  
Adaptive Immune System ◽  
Cell Repertoire ◽  
Cell Receptors

The adaptive immune system recognizes tumor antigens at an early stage to eradicate cancer cells. This process is accompanied by systemic proliferation of the tumor antigen–specific T lymphocytes. While detection of asymptomatic early-stage cancers is challenging due to small tumor size and limited somatic alterations, tracking peripheral T cell repertoire changes may provide an attractive solution to cancer diagnosis. Here, we developed a deep learning method called DeepCAT to enable de novo prediction of cancer-associated T cell receptors (TCRs). We validated DeepCAT using cancer-specific or non-cancer TCRs obtained from multiple major histocompatibility complex I (MHC-I) multimer-sorting experiments and demonstrated its prediction power for TCRs specific to cancer antigens. We blindly applied DeepCAT to distinguish over 250 patients with cancer from over 600 healthy individuals using blood TCR sequences and observed high prediction accuracy, with area under the curve (AUC) ≥ 0.95 for multiple early-stage cancers. This work sets the stage for using the peripheral blood TCR repertoire for noninvasive cancer detection.

scholarly journals Inventories of naive and tolerant mouse CD4 T cell repertoires reveal a hierarchy of deleted and diverted T cell receptors

2019 ◽  
Vol 116 (37) ◽  
pp. 18537-18543 ◽  
Author(s):  
Tobias Hassler ◽  
Emanuel Urmann ◽  
Sebastian Teschner ◽  
Christine Federle ◽  
Thamotharampillai Dileepan ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
T Cell ◽  
T Cell Receptors ◽  
Cd4 T Cell ◽  
Cell Repertoire ◽  
Apparent Lack ◽  
Central Tolerance ◽  
Cell Receptors ◽  
The Central Nervous System ◽  
Antigen Reactivity

Deletion or Tregcell differentiation are alternative fates of autoreactive MHCII-restricted thymocytes. How these different modes of tolerance determine the size and composition of polyclonal cohorts of autoreactive T cells with shared specificity is poorly understood. We addressed how tolerance to a naturally expressed autoantigen of the central nervous system shapes the CD4 T cell repertoire. Specific cells in the tolerant peripheral repertoire either were Foxp3+or displayed anergy hallmarks and, surprisingly, were at least as frequent as in the nontolerant repertoire. Despite this apparent lack of deletional tolerance, repertoire inventories uncovered that some T cell receptors (TCRs) were lost from the CD4 T cell pool, whereas others mediated Tregcell differentiation. The antigen responsiveness of these TCRs supported an affinity model of central tolerance. Importantly, the contribution of different diverter TCRs to the nascent thymic Tregcell population reflected their antigen reactivity rather than their frequency among precursors. This reveals a multilayered TCR hierarchy in CD4 T cell tolerance that separates deleted and diverted TCRs and assures that the Tregcell compartment is filled with cells of maximal permissive antigen reactivity.

scholarly journals Persisting fetal clonotypes influence the structure and overlap of adult human T cell receptor repertoires

2016 ◽  
Author(s):  
Mikhail V Pogorelyy ◽  
Yuval Elhanati ◽  
Quentin Marcou ◽  
Anastasia L Sycheva ◽  
Ekaterina A Komech ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptors ◽  
Cell Receptor ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
The Public ◽  
Human T Cell ◽  
Cell Clones ◽  
Tcr Repertoire ◽  
Low Diversity

The diversity of T-cell receptors recognizing foreign pathogens is generated through a highly stochastic recombination process, making the independent production of the same sequence rare. Yet unrelated individuals do share receptors, which together constitute a “public” repertoire of abundant clonotypes. The TCR repertoire is initially formed prenatally, when the enzyme inserting random nucleotides is downregulated, producing a limited diversity subset. By statistically analyzing deep sequencing T-cell repertoire data from twins, unrelated individuals of various ages, and cord blood, we show that T-cell clones generated before birth persist and maintain high abundances in adult organisms for decades, slowly decaying with age. Our results suggest that large, low-diversity public clones are created during pregnancy, and survive over long periods, providing the basis of the public repertoire.

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