Multimodal profiling of human postnatal thymocytes using CITE-seq
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE271304 | GEO | 2024/07/08
REPOSITORIES: GEO
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Project description:Developing CD4+ T-cells in the thymus mature from CD69+Qa2- cells to CD69-Qa2+ T-cells. This maturation is accombanied by increased expression of CD62L and S1PR1 in Qa2+ cells, which allows mature T-cells to emigrate from the thymus to the periphery. However, miR-142-/- mice are characterized by an altered thymocytes homeostasis, characterized by reduced CD62L protein levels on their cell surface. To characterize the underlying molecular mechanisms, which lead to reduced CD62L expression in miR-142-/- CD4+ thymocytes, we investigated the mRNA levels in immature Qa2- as well as mature Qa2+ thymocytes isolated ex vivo from WT and miR-142 deficient Bl6 mice.
2013-06-14 | GSE47909 | GEO
Project description:Developing CD4+ T-cells in the thymus mature from CD69+Qa2- cells to CD69-Qa2+ T-cells. This maturation is accombanied by increased expression of CD62L and S1PR1 in Qa2+ cells, which allows mature T-cells to emigrate from the thymus to the periphery. However, miR-142-/- mice are characterized by an altered thymocytes homeostasis, characterized by reduced CD62L protein levels on their cell surface. To characterize the underlying molecular mechanisms, which lead to reduced CD62L expression in miR-142-/- CD4+ thymocytes, we investigated the mRNA levels in immature Qa2- as well as mature Qa2+ thymocytes isolated ex vivo from WT and miR-142 deficient Bl6 mice. Thymi were isolated from a pool of 4-5 mice per genotype and cells were isolated by FACS sorting. After sorting, total mRNA was isolated and expression levels were investigated with an Affymetrix microarrage Gene 1.0ST chip.
2013-06-14 | E-GEOD-47909 | biostudies-arrayexpress
Project description:BACKGROUND: The thymus is a central lymphoid organ, in which bone marrow-derived T cell precursors undergo a complex process of maturation. Developing thymocytes interact with thymic microenvironment in a defined spatial order. A component of thymic microenvironment the thymic epithelial cells (TEC) are crucial for the maturation of T-lymphocytes because the secretion of extracellular matrix compounds, thymic hormones and cytokines and also by cell-cell contacts which can be mediated by extracellular matrix compounds and its receptors, integrins. There is evidence that extracellular matrix molecules play a fundamental role in localizing the different thymocyte stages in the thymus. The interaction between alpha5beta1 (CD49e/CD29; VLA-5) and fibronectin is essential for thymocyte adhesion. Previous results from our laboratory have shown that adhesion of thymocytes to cultured TEC line is enhanced in the presence of fibronectin. And we also demonstrated that anti-VLA-5 antibody when applied to growing TEC prior to the co-culturing with thymocytes, significantly prevented their adhesion to the epithelial. RESULTS: Herein, we studied the role of integrin alpha5 subunit in thymocyte and thymic epithelial cell interactions. We investigate the in vitro effects of silencing alpha5 integrin subunit in human thymic epithelial cell line by RNA interference. After silence a great deal of interest has arisen on intracellular signaling due the absence of alpha5 integrin subunit silence. The expression profile using cDNA microarrays of alpha5 subunit silenced cells showed 131 genes differential expression. Our data showed downregulation in two genes with cell adhesion function: neuronal cell adhesion molecule (NrCAM) and Activin receptor-like kinase 1 gene and in genes related with integrin pathway like, Phosphatidylinositol-4-phosphate 5-kinase, Phospholipase C gamma1 and SHC (Src homology 2 domain containing) transforming protein 1. We also assessed the effect of the loss of alpha5beta1 expression on TEC-thymocytes interaction and ours experiments confirm that alpha5beta1 contribute to adhesion rate. CONCLUSION: Conjointly, our data reinforce the importance of VLA-5 in TEC thymocyte interactions in the process of thymocyte differentiation and we hypothesize a decrease in stress fibers due absence of alpha5 integrin subunit and a compensatory pathway because of downregulation of neuropilin-2, vascular endothelial growth factor and plexin A.
2010-02-28 | GSE18116 | GEO
Project description:Human T-cell development is less well studied than its murine counterpart due to the lack of genetic tools and the difficulty of obtaining cells and tissues. However, recent technological advances allow identification of the transcriptional landscape of differentiating human thymocytes. Here we report the gene expression profiles of 11 immature, consecutive T-cell developmental stages. The changes in gene expression of cultured stem cells on OP9-DL1 match those of ex vivo isolated human thymocytes. These analyses led us to define evolutionary conserved gene signatures that represent pre- and post- αβ T-cell commitment stages. We found that loss of CD44 marks T-cell commitment in early CD7+CD5+CD45dim cells, before the acquisition of CD1a surface expression. The CD44-CD1a- post-committed thymocytes have initiated in frame TCR rearrangements and have completely lost the capacity to develop into myeloid, B- and NK-cells, unlike uncommitted CD44+CD1a- thymocytes. Therefore, loss of CD44 represents a previously unrecognized stage that defines the earliest committed T-cell population in the human thymus. We used microarrays to detail the transcriptional program underlying human early T-cell differentiation, from CD34+ HSCs until the CD4+CD8+ DP stage.
2017-03-08 | GSE79379 | GEO
Project description:In the earliest step of thymic organogenesis, mesenchymal cells support the growth of thymic epithelial cells (TECs). It is established that TECs and thymocytes influence each other for their growth/differentiation, a process called thymic crosstalk. However, little is known about the influence of developing thymocytes or TECs on mesenchymal cells. Here, we show that during normal thymus development fibroblast ingrowth occurs towards hypoxic areas. Similar overgrowth of mesenchymal cells is seen in a fetal thymic organ culture system under low oxygen conditions. However, when thymocytes were depleted by deoxyguanosine treatment, mesenchymal cells were also induced, precluding the direct effect of hypoxia. In the fetal thymus of hCD3εTg mice, which lack T lineage cells, an overgrowth of mesenchymal cells can be seen at a very early stage of thymic organogenesis. The growth of the mesenchymal cells is due to extensive proliferation and not mere enrichment. With RNA sequencing analysis comparing hCD3εTg with wild type TECs, we identified candidate factors that could be involved in mesenchymal network formation.
2017-08-19 | GSE60520 | GEO
Project description:In the mouse thymus, invariant γδ T cells are generated at well-defined times during development and acquire effector functions before exiting the thymus. However, whether such thymic programming can occur in human is not known. Here we analyzed human fetal and post-natal γδ thymocytes and investigated the role of hematopoietic-stem-and-precursor-cells (HSPC) in the generation of human γδ T cells. Unlike post-natal γδ thymocytes, fetal γδ thymocytes were functionally programmed (e.g. IFNγ, granzymes), expressed low levels of terminal-deoxynucleotidyl-transferase (TdT) and were highly enriched for invariant/public germline-encoded CDR3 sequences (TRGV8-TRJP1-CATWDTTGWFKIF, TRDV2-TRDD3-CACDTGGY and TRDV1-TRDD3-CALGELGD, previously shown to be expanded in cytomegalovirus infection) composed of short-homology-repeat-containing gene segments. Furthermore, these unique characteristics were due to an intrinsic property of fetal HSPC caused by high expression of the RNA-binding protein Lin28b. In conclusion, our data indicate that the human fetal thymus generates, in a HSPC/Lin28b-dependent manner, invariant γδ T cells with programmed effector functions.
2019-11-21 | GSE128163 | GEO
Project description:The thymus is essential for establishing adaptive immunity yet undergoes age-related involution that leads to compromised immune responsiveness. The thymus is also extremely sensitive to acute insult and although capable of regeneration, this capacity declines with age for unknown reasons. We applied single-cell and spatial transcriptomics, lineage-tracing and advanced imaging to define age-related changes in non-hematopoietic stromal cells and discovered the emergence of two atypical thymic epithelial cell (TEC) states. These age-associated (aa)TECs formed high-density peri-medullary epithelial clusters that were devoid of thymocytes; an accretion of non-productive thymic tissue that worsened with age, exhibited features of epithelial-to-mesenchymal transition (EMT), and was associated with downregulation of FOXN1. Interaction analysis revealed that the emergence of aaTEC drew tonic signals from other functional TEC populations at baseline acting as a sink for TEC growth factors. Following acute injury, aaTEC expanded substantially, further perturbing trophic regeneration pathways and correlating with defective repair of the involuted thymus. These findings therefore define a unique feature of thymic involution linked to immune aging and could have implications for developing immune boosting therapies in older individuals.
2024-06-27 | GSE249752 | GEO
Project description:The thymus is essential for establishing adaptive immunity yet undergoes age-related involution that leads to compromised immune responsiveness. The thymus is also extremely sensitive to acute insult and although capable of regeneration, this capacity declines with age for unknown reasons. We applied single-cell and spatial transcriptomics, lineage-tracing and advanced imaging to define age-related changes in non-hematopoietic stromal cells and discovered the emergence of two atypical thymic epithelial cell (TEC) states. These age-associated (aa)TECs formed high-density peri-medullary epithelial clusters that were devoid of thymocytes; an accretion of non-productive thymic tissue that worsened with age, exhibited features of epithelial-to-mesenchymal transition (EMT), and was associated with downregulation of FOXN1. Interaction analysis revealed that the emergence of aaTEC drew tonic signals from other functional TEC populations at baseline acting as a sink for TEC growth factors. Following acute injury, aaTEC expanded substantially, further perturbing trophic regeneration pathways and correlating with defective repair of the involuted thymus. These findings therefore define a unique feature of thymic involution linked to immune aging and could have implications for developing immune boosting therapies in older individuals.
2024-06-27 | GSE249753 | GEO
Project description:The thymus is essential for establishing adaptive immunity yet undergoes age-related involution that leads to compromised immune responsiveness. The thymus is also extremely sensitive to acute insult and although capable of regeneration, this capacity declines with age for unknown reasons. We applied single-cell and spatial transcriptomics, lineage-tracing and advanced imaging to define age-related changes in non-hematopoietic stromal cells and discovered the emergence of two atypical thymic epithelial cell (TEC) states. These age-associated (aa)TECs formed high-density peri-medullary epithelial clusters that were devoid of thymocytes; an accretion of non-productive thymic tissue that worsened with age, exhibited features of epithelial-to-mesenchymal transition (EMT), and was associated with downregulation of FOXN1. Interaction analysis revealed that the emergence of aaTEC drew tonic signals from other functional TEC populations at baseline acting as a sink for TEC growth factors. Following acute injury, aaTEC expanded substantially, further perturbing trophic regeneration pathways and correlating with defective repair of the involuted thymus. These findings therefore define a unique feature of thymic involution linked to immune aging and could have implications for developing immune boosting therapies in older individuals.
2024-06-27 | GSE240017 | GEO
Project description:The thymus is essential for establishing adaptive immunity yet undergoes age-related involution that leads to compromised immune responsiveness. The thymus is also extremely sensitive to acute insult and although capable of regeneration, this capacity declines with age for unknown reasons. We applied single-cell and spatial transcriptomics, lineage-tracing and advanced imaging to define age-related changes in non-hematopoietic stromal cells and discovered the emergence of two atypical thymic epithelial cell (TEC) states. These age-associated (aa)TECs formed high-density peri-medullary epithelial clusters that were devoid of thymocytes; an accretion of non-productive thymic tissue that worsened with age, exhibited features of epithelial-to-mesenchymal transition (EMT), and was associated with downregulation of FOXN1. Interaction analysis revealed that the emergence of aaTEC drew tonic signals from other functional TEC populations at baseline acting as a sink for TEC growth factors. Following acute injury, aaTEC expanded substantially, further perturbing trophic regeneration pathways and correlating with defective repair of the involuted thymus. These findings therefore define a unique feature of thymic involution linked to immune aging and could have implications for developing immune boosting therapies in older individuals.
2024-06-27 | GSE240016 | GEO