scholarly journals A cell atlas of human thymic development defines T cell repertoire formation

Science ◽  
2020 ◽  
Vol 367 (6480) ◽  
pp. eaay3224 ◽  
Author(s):  
Jong-Eun Park ◽  
Rachel A. Botting ◽  
Cecilia Domínguez Conde ◽  
Dorin-Mirel Popescu ◽  
Marieke Lavaert ◽  
...  
Keyword(s):  
T Cell ◽  
Life Span ◽  
Cell Types ◽  
Cell Receptor ◽  
Cell Repertoire ◽  
Thymic Development ◽  
Human Thymus ◽  
Human T Cell ◽  
A Cell

The thymus provides a nurturing environment for the differentiation and selection of T cells, a process orchestrated by their interaction with multiple thymic cell types. We used single-cell RNA sequencing to create a cell census of the human thymus across the life span and to reconstruct T cell differentiation trajectories and T cell receptor (TCR) recombination kinetics. Using this approach, we identified and located in situ CD8αα+ T cell populations, thymic fibroblast subtypes, and activated dendritic cell states. In addition, we reveal a bias in TCR recombination and selection, which is attributed to genomic position and the kinetics of lineage commitment. Taken together, our data provide a comprehensive atlas of the human thymus across the life span with new insights into human T cell development.

scholarly journals A cell atlas of human thymic development defines T cell repertoire formation

2020 ◽  
Author(s):  
Jong-Eun Park ◽  
Rachel A. Botting ◽  
Cecilia Domínguez Conde ◽  
Dorin-Mirel Popescu ◽  
Marieke Lavaert ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lineage ◽  
Cell Types ◽  
Cell Receptor ◽  
Cell Repertoire ◽  
Thymic Development ◽  
Human Thymus ◽  
Human T Cell ◽  
A Cell

AbstractThe thymus provides a nurturing environment for the differentiation and selection of T cells, a process orchestrated by their interaction with multiple thymic cell types. We utilised single-cell RNA-sequencing (scRNA-seq) to create a cell census of the human thymus and to reconstruct T-cell differentiation trajectories and T-cell receptor (TCR) recombination kinetics. Using this approach, we identified and located in situ novel CD8αα+ T-cell populations, thymic fibroblast subtypes and activated dendritic cell (aDC) states. In addition, we reveal a bias in TCR recombination and selection, which is attributed to genomic position and suggests later commitment of the CD8+ T-cell lineage. Taken together, our data provide a comprehensive atlas of the human thymus across the lifespan with new insights into human T-cell development.

scholarly journals Development of a diverse human T-cell repertoire despite stringent restriction of hematopoietic clonality in the thymus

2015 ◽  
Vol 112 (44) ◽  
pp. E6020-E6027 ◽  
Author(s):  
Martijn H. Brugman ◽  
Anna-Sophia Wiekmeijer ◽  
Marja van Eggermond ◽  
Ingrid Wolvers-Tettero ◽  
Anton W. Langerak ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Development ◽  
Xenograft Model ◽  
Subsequent Development ◽  
Cell Receptor ◽  
Cell Development ◽  
Cell Repertoire ◽  
Hematopoietic Stem ◽  
Human T Cell ◽  
Hsc Transplantation

The fate and numbers of hematopoietic stem cells (HSC) and their progeny that seed the thymus constitute a fundamental question with important clinical implications. HSC transplantation is often complicated by limited T-cell reconstitution, especially when HSC from umbilical cord blood are used. Attempts to improve immune reconstitution have until now been unsuccessful, underscoring the need for better insight into thymic reconstitution. Here we made use of the NOD-SCID-IL-2Rγ−/− xenograft model and lentiviral cellular barcoding of human HSCs to study T-cell development in the thymus at a clonal level. Barcoded HSCs showed robust (>80% human chimerism) and reproducible myeloid and lymphoid engraftment, with T cells arising 12 wk after transplantation. A very limited number of HSC clones (<10) repopulated the xenografted thymus, with further restriction of the number of clones during subsequent development. Nevertheless, T-cell receptor rearrangements were polyclonal and showed a diverse repertoire, demonstrating that a multitude of T-lymphocyte clones can develop from a single HSC clone. Our data imply that intrathymic clonal fitness is important during T-cell development. As a consequence, immune incompetence after HSC transplantation is not related to the transplantation of limited numbers of HSC but to intrathymic events.

Analysis of the Human T Cell Receptor (TCR) Repertoire from Birth to Old Age Suggests That TCRVβfrequencies Are Established Independent of HLA.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3313-3313
Author(s):  
J. Joseph Melenhorst ◽  
Josette Zeilah ◽  
Edgardo Sosa ◽  
Dean Follmann ◽  
Nancy F. Hensel ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Protein Expression ◽  
Rank Order ◽  
Cell Receptor ◽  
T Cell Subsets ◽  
Rank Test ◽  
Cell Repertoire ◽  
Cd8 Cells ◽  
Human T Cell

Abstract Human T cell development occurs in two waves of development and proliferation: first, early T cells expressing the TCRb chain but not the α-chain are selected for functional TCRβ protein independent of HLA recognition, a process called β-selection; second, thymocytes expressing both the α- and β-TCR are selected for intermediate affinity for self-MHC/ self-peptide complex. This latter process is referred to as positive selection. We sought to determine whether the peripheral TCRVβ frequencies in the naïve T cell repertoire start off at a fixed rank order with minimal skewing as would be expected from a predominantly β-selected repertoire. A total of 22 TCRVβ proteins was quantitated by flow cytometry in a group of 20 unselected umbilical cord blood (UCB) samples (a kind gift from Dr. P. Rubinstein, NY Blood Center, NY), consisting of &gt;80% naïve T cells as defined by CD27+CD45RA+ staining in CD4+ and CD8+ cells. A common rank order of TCRVβ protein frequencies was found in both CD4 and CD8 T cell subsets (figure 1). Median TCRVβ frequencies in CD4 and in CD8 cells of UCB were statistically not significantly different from the frequencies in adult donor CD4 and CD8 cells (Wilcoxon signed rank test; p &gt; 0.2). Furthermore, the percentages of CD4 cells expressing a particular Vβ correlated significantly in CD8 cells (figure 2) with some Vβ proteins being predominantly expressed by either CD4 (Vβ2, Vβ5.1) or CD8 (Vβ14, Vβ7) cells. Our data therefore conform to the prediction that the TCRVβ frequencies are dominantly shaped by β-selection, and not by interactions of the αβTCR/ co-receptor with MHC/ antigen complexes during thymic selection. Figure 1. TCRBV in UCB CD4+ (top) and CD8+ (bottom) T cells Figure 1. TCRBV in UCB CD4+ (top) and CD8+ (bottom) T cells Figure 2. Comparison of TCRBV protein expression frequencies in CD4 and CD8 cells of UCB Figure 2. Comparison of TCRBV protein expression frequencies in CD4 and CD8 cells of UCB

scholarly journals Early human T cell development: analysis of the human thymus at the time of initial entry of hematopoietic stem cells into the fetal thymic microenvironment.

1995 ◽  
Vol 181 (4) ◽  
pp. 1445-1458 ◽  
Author(s):  
B F Haynes ◽  
C S Heinly
Keyword(s):  
Stem Cells ◽  
T Cell ◽  
Hematopoietic Stem Cells ◽  
T Cell Development ◽  
Fold Increase ◽  
Cell Receptor ◽  
Cell Development ◽  
Hematopoietic Stem ◽  
Human Thymus ◽  
Human T Cell

To determine events that transpire during the earliest stages of human T cell development, we have studied fetal tissues before (7 wk), during (8.2 wk), and after (9.5 wk to birth) colonization of the fetal thymic rudiment with hematopoietic stem cells. Calculation of the approximate volumes of the 7- and 8.2-wk thymuses revealed a 35-fold increase in thymic volumes during this time, with 7-wk thymus height of 160 microM and volume of 0.008 mm3, and 8.2-wk thymus height of 1044 microM and volume of 0.296 mm3. Human thymocytes in the 8.2-wk thymus were CD4+ CD8 alpha+ and cytoplasmic CD3 epsilon+ cCD3 delta+ CD8 beta- and CD3 zetta-. Only 5% of 8-wk thymocytes were T cell receptor (TCR)-beta+, &lt; 0.1% were TCR-gamma+, and none reacted with monoclonal antibodies against TCR-delta. During the first 16 wk of gestation, we observed developmentally regulated expression of CD2 and CD8 beta (appearing at 9.5 wk), CD1a,b, and c molecules (CD1b, then CD1c, then CD1a), TCR molecules (TCR-beta, then TCR-delta), CD45RA and CD45RO isoforms, CD28 (10 wk), CD3 zeta (12-13 wk), and CD6 (12,75 wk). Whereas CD2 was not expressed at the time of initiation of thymic lymphopoiesis, a second CD58 ligand, CD48, was expressed at 8.2 wk, suggesting a role for CD48 early in thymic development. Taken together, these data define sequential phenotypic and morphologic changes that occur in human thymus coincident with thymus colonization by hematopoietic stem cells and provide insight into the molecules that are involved in the earliest stages of human T cell development.

scholarly journals T cell receptor alpha chain genes are located on chromosome 14 at 14q11-14q12 in humans.

1985 ◽  
Vol 161 (5) ◽  
pp. 1255-1260 ◽  
Author(s):  
N Caccia ◽  
G A Bruns ◽  
I R Kirsch ◽  
G F Hollis ◽  
V Bertness ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Chromosome 14 ◽  
Receptor Alpha ◽  
Alpha Chain ◽  
Human T Cell ◽  
Receptor Alpha Chain ◽  
Cell Receptor Alpha

A cDNA clone encoding the alpha chain of the human T cell receptor was used in connection with somatic cell human-rodent hybrids to determine that the genes coding for the alpha chain are located on chromosome 14 in humans. In situ hybridization confirms this result and further localizes these genes to 14q11-14q12 on this chromosome. Since this region of chromosome has been shown to be nonrandomly involved in a number of T cell neoplasias, this assignment raises a number of interesting questions as to the possible involvement of the T cell receptor alpha chain genes in tumorigenesis.

scholarly journals Localization of T cell clonotypes using spatial transcriptomics

2021 ◽  
Author(s):  
William H. Hudson ◽  
Lisa J. Sudmeier
Keyword(s):  
T Cell ◽  
Spatial Organization ◽  
Spatial Information ◽  
Human Tumor ◽  
Cell Receptor ◽  
Cell Repertoire ◽  
T Cell Clones ◽  
Human T Cell ◽  
Cell Clones ◽  
Archived Samples

Spatial transcriptomics is an emerging technology that measures gene expression while preserving spatial information. Here, we present a method to determine localization of specific T cell clones by obtaining T cell receptor (TCR) sequences from spatial transcriptomics assays. Our method uses an existing commercial spatial transcriptomics platform and open-source software for analysis, allowing simple and inexpensive integration with archived samples and existing laboratory workflows. Using human brain metastasis samples, we show that TCR sequences are readily obtained from human tumor tissue and that these sequences are recapitulated by single-cell sequencing methods. This technique will permit detailed studies of the spatial organization of the human T cell repertoire, such as the identification of tumor- infiltrating and tumor-excluded T cell clones.

scholarly journals Early life imprints the hierarchy of T cell clone sizes

2020 ◽  
Author(s):  
Mario U. Gaimann ◽  
Maximilian Nguyen ◽  
Jonathan Desponds ◽  
Andreas Mayer
Keyword(s):  
T Cell ◽  
Time Window ◽  
Cell Clone ◽  
Clonal Selection ◽  
Scaling Law ◽  
Cell Receptor ◽  
Sequencing Data ◽  
Cell Repertoire ◽  
Human T Cell ◽  
T Cell Clone

The adaptive immune system responds to pathogens by selecting clones of cells with specific receptors. While clonal selection in response to particular antigens has been studied in detail, it is unknown how a lifetime of exposures to many antigens collectively shape the immune repertoire. Here, through mathematical modeling and statistical analyses of T cell receptor sequencing data we demonstrate that clonal expansions during a perinatal time window leave a long-lasting imprint on the human T cell repertoire. We demonstrate how the empirical scaling law relating the rank of the largest clones to their size can emerge from clonal growth during repertoire formation. We statistically identify early founded clones and find that they are indeed highly enriched among the largest clones. This enrichment persists even after decades of human aging, in a way that is quantitatively predicted by a model of fluctuating clonal selection. Our work presents a quantitative theory of human T cell dynamics compatible with the statistical laws of repertoire organization and provides a mechanism for how early clonal dynamics imprint the hierarchy of T cell clone sizes with implications for pathogen defense and autoimmunity.

Localization of the human T-cell receptor gamma locus (TCRG) to 7p14→p15 by in situ hybridization

1991 ◽  
Vol 56 (1) ◽  
pp. 31-32 ◽  
Author(s):  
M. Bensmana ◽  
M.G. Mattei ◽  
M.-P. Lefranc
Keyword(s):  
In Situ Hybridization ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Human T Cell ◽  
Gamma Locus
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