Exome sequencing of thymus transplantation based spontaneous murine T cell acute lymphoblastic leukemia (T-ALL) model
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE137179 | GEO | 2019/09/10
REPOSITORIES: GEO
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Project description:We adapted a spontaneously-arising, genetically-heterogeneous, thymic transplantation-based murine model of T-ALL, recapitulating key histopathological and genetic features of the human disease, to the preclinical testing of targeted and immune-directed therapies.
2019-09-07 | GSE137057 | GEO
Project description:Exome sequencing of thymus transplantation based spontaneous murine T cell acute lymphoblastic leukemia (T-ALL) model
| PRJNA564896 | ENA
Project description:Here we report the isolation of a murine model for heritable T cell lymphoblastic leukemia/lymphoma (T-ALL) called Spontaneous dominant leukemia (Sdl). Sdl heterozygous mice develop disease with a short latency and high penetrance; while mice homozygous for the mutation die early during embryonic development. Sdl mice harbor increased numbers of spontaneous micronuclei, and Sdl T-ALLs harbor small amplifications and deletions, including activating deletions at the Notch1 locus. Sdl mice harbor a spontaneously acquired mutation in Mcm4 (Mcm4D573H). MCM4 is part of the heterohexameric complex of MCM2-7 that is important for licensing of DNA origins prior to S phase and also serves as the core of the replicative helicase that unwinds DNA at the replication fork. This exon array was conducted to determine the expression changes that occur in pre-leukemic thymus samples at 21 days of age, as well as thymic tumors in the Sdl model. generated pairwise comparisons of wild-type > pre-leukemic and wild-type > thymic tumor. Transcripts with a posterior probability of differential expression >95% and a q-value < 0.05 were considered to be significantly differentially expressed.
2012-09-01 | E-GEOD-40527 | biostudies-arrayexpress
Project description:Presentation of tissue-restricted antigens (TRA) in the thymus is essentialfor establishing self-tolerancethrough elimination of autoreactive Tcells.It remains unclear why certain self T cells can bypassthymic selectionand become driversoftissue-specific autoimmunity. Herewe assessedthymic TRA presented by a major histocompatibility class II molecule (MHC-II) that confers genetic propensity to develop type 1 diabetes. This analysisestablished the thymic peptidome containing self-peptidesderivedfrom variousperipheral tissues,butalso revealed a disparity in the MHC-II epitoperepertoirebetween thymus and the target site of autoimmunity, the pancreatic islets.The thymic repertoire consistedof canonicalMHC-IIepitopes capable of enforcing central tolerance but lacked presentation of uniqueepitopes derived from unconventionalself-proteinprocessing orneoepitopes formed by post-translational modifications. Suchepitopes were noteworthily generatedin the isletsvia a tissue-intrinsic mechanism, crinophagy, and were recognized by CD4 T cells escaping central tolerance.These findings supportthat central tolerance mechanisms are effective but incomplete, as tissue-characteristic handling of self-antigens may broaden the peripheralrepertoire thatextends beyond the scope of thymic selection.
2024-08-22 | PXD030999 | Pride
Project description:Single cell RNA sequencing of immune and non-immune cells from healthy ageing thymus
Thymus is a primary lymphoid organ that creates an environment for the T lymphocyte precursors differentiation into the naive T cells, which involves TCR gene rearrangement, negative and positive selection. Despite thymus critical function for the recognition of the pathogens it starts to atrophy very early in life. Thymic Epithelial Space (TES), where thymocyte education occurs, starts to decline rapidly just after birth, while with the onset of puberty thymus is also progressively replaced with adipose tissue. This leads to a reduced naive T cell output,which decreases an organism's ability to recognize pathogens.
In our lab, we have already collected and characterized cell type composition and gene regulatory networks of the fetal tand adult human thymus (Park et al, Science 2020). In the current project we plan to expand the number of paediatric and adult samples in the study with the aim to understand how the process of thymic involution happens. We will use single-cell transcriptomics to zoom on changes that occur in immune and non-immune cell types in different phases of thymic involution with the hope to understand which gene expression changes are causal for the thymic involution process and how naïve T cell production can be increased in elderly.
This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/
| EGAS00001004311 | EGA
Project description:Transcriptome analysis was performed on the thymus of necropsied Japanese Black calves with a poor prognosis, to clarify the pathology of acute thymic involution, which often happens in farmed calves with a poor prognosis. Gene expression profiles obtained by DNA microarray analysis of eight calf thymuses were grouped into three patterns associated with the histopathological classification of acute thymic involution. Three clusters were arranged by the stage of acute thymic involution based on the first principal component score, suggesting that histopathological conditions have the most significant impact on changes in gene expression profile.
2024-08-18 | GSE269843 | GEO
Project description:The thymus is one of the most affected organs during malnutrition, exhibiting atrophy and thymocyte depletion, characteristics that are also observed in several infectious diseases. The detrimental effects of malnutrition on immune responses to pathogens have long been recognized and it is considered a main risk factor for various infectious diseases, including visceral leishmaniasis (VL). However, the thymus has been barely studied during malnutrition and Leishmania infantum infection association. Protein malnutrition modifies intrathymic communication in L. infantum infected BALB/c mice by altering the abundance of proteins secreted to the thymic interstitial fluid (IF). We identified and compared protein abundance in the thymic IF samples from BALB/c mice that were fed with control protein (14%, CP) or low protein (4%, LP) isocaloric diets, followed by infection with L. infantum. By means of a quantitative proteomics approach using iTRAQ we identified 280 proteins of which 81% were reported as secreted by exosomes and 42% were previously described as secreted by thymic epithelial cells. LP-infected (LPi) animals showed a significant decrease in exosomal proteins, suggesting that exosomal carrier system is dysregulated in malnourished animals. LPi mice also exhibited an increase in the relative abundance of proteins involved in lipid metabolism and tricarboxylic acid cycle, suggestive of a non-proliferative microenvironment. Accordingly, flow cytometry analysis revealed that protein malnutrition decreases the proliferation of single positive and double positive T cells. Proteins engaged in glycolysis, protein ubiquitination and mRNA processing were significantly decreased. In addition, a significant decrease in the abundance of galectin-1 and increase of plasminogen were observed in malnourished animals. Together, the reduced cortical area, decreased proliferation, increased abundance of lipid- and tricarboxylic acid cycle-related proteins, and altered abundance of galectin-1 and plasminogen indicate a dysfunctional thymic microenvironment, where T cell migration, proliferation and maturation are compromised, contributing for the thymic atrophy observed in malnourished animals. All these alterations affect the control of the local and systemic infection, resulting in an impaired response to L. infantum infection.
2019-11-12 | PXD010414 | Pride
Project description:The mechanism of egress of mature regulatory T cells (Tregs) from the thymus to the periphery remains enigmatic, as does the nature of those factors expressed in the thymic environment. Here, we examined the fate of thymic Tregs in TNFα/RelA double-knockout (TA-KO) mice, because TA-KO mice retain a Treg population in the thymus but have only a small Treg population at the periphery. Transplantation of whole TA-KO thymus to under the kidney capsule of Rag1 null mice failed to induce the production of donor-derived splenic Tregs expressing neuropilin-1 (Nrp1), which was reported to be a marker of naturally occurring Tregs, indicating that TA-KO thymic Tregs either do not leave the thymus or are lost at the periphery. We next transplanted enriched TA-KO thymic Tregs to the peripheries of TA-KO mice and traced mouse survival. Transplantation of TA-KO thymic Tregs rescued the lethality in TA-KO mice, demonstrating that TA-KO thymic Tregs remain functional at the periphery. The TA-KO thymic Treg population had highly demethylated CpG motifs in the foxp3 locus, indicating that the cells were arrested at a late-mature stage. Also, the population included a large subpopulation of Tregs expressing IL-7Rα, which is a possible marker of late-mature Tregs. Finally, TA-KO fetal liver chimeric mice developed an Nrp1+ splenic Treg population from TA-KO cells, suggesting that Treg arrest is caused by a lack of RelA in the thymic environment. Together, these results suggest that egress of mature Tregs from the thymus depends on RelA in the thymic environment. For the isolation of thymic Tregs, CD4+CD8α-CD25hi thymocytes were isolated from five 1.5- to 2-week-old TNFα-KO or TA-KO mice by using a FACSAria cell sorter. For the isolation of thymic stromal cells, 10 thymi from 1.5- to 2-week-old TNFα-KO or TA-KO mice were minced with scissors and treated with RPMI 1640 supplemented with 2% FCS, 0.2 mg/ml collagenase (Roche, Basel, Switzerland), 0.2 mg/ml dispase I (Roche), and 100 U/ml DNase I (Life Technologies) for 30 min with stirring. Digested thymi were centrifuged in a Percoll (GE Healthcare Bio-Sciences, Piscataway, NJ, USA) gradient (density, 1.115, 1.065, and PBS) at 1400g for 30 min. Cells in the upper layer were collected, and the CD45-EpCAM+ (thymic epithelial cells) and CD45+EpCAM- populations (enriched thymic stromal cells containing macrophages or dendritic cells) were sorted.
2015-03-04 | E-GEOD-64191 | biostudies-arrayexpress
Project description:The thymic stroma provides the microenvironment for T cell lineage commitment, development, maturation, and repertoire selection. While the thymic epithelial cell (TEC) compartment is relatively well characterised, a comparably detailed analysis of the non-TEC stromal compartment including the endothelial cells and fibroblasts is currently lacking. Here, we probe the composition of thymic mesenchymal cells and their dynamic change during thymus organogenesis. Using a single cell transcriptomic approach, we identify previously unappreciated heterogeneity within the non-TEC stromal compartment and demonstrate dynamic shifts within non-TEC stromal cell populations over thymic development. We then use a compound heterozygous model (Tbx1+/-Crkl+/-) for 22q11.2DS syndrome to show that significant reductions of multiple mesenchymal subpopulations associated with functional defects and accelerated aging are associated with the thymic hypoplasia observed in this condition. Thus, we provided a comprehensive picture of non-TEC thymic stromal development and their functional defects in a disease model of thymic hypoplasia.
2022-05-13 | GSE163520 | GEO