Dynamic Changes in Lymphocyte Populations Establish Zebrafish as a Thymic Involution Model
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PROVIDER: PRJNA994052 | ENA |
REPOSITORIES: ENA
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Project description:The thymus is the site of T lymphocyte development and T cell education to recognize foreign, but not self, antigens. B cells also reside and develop in the thymus, although their function(s) are less clear. During ‘thymic involution,’ a process of lymphoid atrophy and adipose replacement linked to sexual maturation, thymic cells decline. However, thymic B cells decrease far less than T cells, such that B cells comprise ~1% of neonatal thymocytes, but up to ~10% in adulthood in humans. All jawed vertebrates possess a thymus, and we and others have shown that zebrafish (Danio rerio) also have thymic B cells. Here, we investigated the precise identities of zebrafish thymic T and B cells and how they change with involution. We assessed the timing and specific details of zebrafish thymic involution using multiple lymphocyte-specific, fluorophore-labeled transgenic lines, quantifying changes in thymic lymphocytes pre- vs. post-involution. Our results prove that, as in humans, zebrafish thymic B cells increase relative to T cells post-involution. We also performed RNA sequencing (RNA-seq) on D. rerio thymic and marrow lymphocytes of four novel double-transgenic lines, identifying distinct populations of immature T and B cells. Collectively, this is the first comprehensive analysis of zebrafish thymic involution, demonstrating its similarity to human involution, and establishing the highly genetically-manipulatable zebrafish model as a template for involution studies.
2024-04-02 | GSE237139 | GEO
Project description:Given its central role in immune aging, identifying regulators of thymic involution is important. While conventional programmed cell death plays a fundamental role in thymocyte development, how cell death pathways contribute to thymic involution remains unclear. In this study, we found that CD4+CD8+ double positive (DP) thymocytes acquired characteristics of senescence in aged mice undergoing thymic involution, while expression of the m6A methyltransferase METTL3 (enriched in DP cells from young mice) decreased with aging. By conditionally deleting METTL3 in T cells, we revealed a critical role for METTL3 in DP cell survival, and in restraining features of aging in DP thymocytes by preventing ferroptosis signaling, through glutathione peroxidase 4 (GPX4). Mechanistically, GPX4 was maintained by METTL3 at the translational level, independent of its methyltransferase activity. Furthermore, we found that pharmacological inhibition of ferroptosis promoted DP cell survival, and attenuate d features of aging in DP thymocytes. These findings uncover a role for METTL3-regulated ferroptosis in thymic involution, and identify strategies to restore thymic function.
2024-08-18 | GSE271324 | GEO
Project description:The thymic microenvironment is essential for proper differentiation and selection of thymocytes.Thymic involution in aged mice results in decreased T cell output and immune function. Here we use gene expression profiling of FACS sorted thymic stromal subsets to identify molecular mediators of thymocyte: stromal cell interactions, as well as gene expression changes thymic stromal subsets during early stages of thymic involution . We used microarrays to analyze gene expression differences between thymic stromal subsets from male C57BL/6J mice 1, 3, and 6 months of age.
2014-09-12 | GSE56928 | GEO
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 thymic microenvironment is essential for proper differentiation and selection of thymocytes.Thymic involution in aged mice results in decreased T cell output and immune function. Here we use gene expression profiling of FACS sorted thymic stromal subsets to identify molecular mediators of thymocyte: stromal cell interactions, as well as gene expression changes thymic stromal subsets during early stages of thymic involution . We used microarrays to analyze gene expression differences between thymic stromal subsets from male C57BL/6J mice 1, 3, and 6 months of age. Thymic stromal subsets (cTEC, mTEClo, mTEChi, Sirpa-DC, Sirpa+DC, and fibroblasts) were isolated from two 1-, 3-, and 6- month old male C57BL/6J mice. After enzymatic digestion of the thymi, the stromal cells were FACS purified, and RNA was extracted, amplified, labeled and hybridized to Affymetrix mouse 430 2.0 arraysarrays. Raw data were uploaded to Gene Expression Commons for normalization. Both raw CEL and normalized datasets from the 36 samples are included. A model within Gene Expression Commons has been created for analyses/comparisons of these datasets, along with previously reported thymocyte subset datasets. The model within Gene Expression Commons thus contains 6 thymic stromal populations, each from mice 1, 3, and 6 months of age, with duplicates for each datset.
2014-09-12 | E-GEOD-56928 | biostudies-arrayexpress
Project description:Genetic modeling of thymic involution has demonstrated the importance of individual inflammatory pathways affecting the thymic microenvironment, particularly thymic epithelial cells (TEC). We studied the pathogenic processes in chronological aging of the murine thymus. We used microarrays to elucidate the global gene expression and to identify a leading edge subset of age-associated genes in TEC. Analyses of the TEC transcriptome demonstrated altered expression associated with inflammatory and fatty acid metabolism.
2016-05-06 | GSE81163 | GEO
Project description:In this study, we collected mice thymus at the age of 1 month, 3 months, and 6 months for sequencing to observe the lncRNA and gene expression profiles in the early stage of thymic involution. RNA-sequencing showed that 340 and 152 differentially expressed genes (DEGs) overlapped at 3- and 6-month-old groups compared with 1-month-old group in males and females, respectively. GO analysis showed that DEGs were significantly enriched in immune response activation, cell proliferation, and fatty acid metabolic process, etc. Next, we identified 15 causal transcription factors. Meanwhile, we identified 16 key DEGs and 29 differentially expressed lncRNAs (DEL), which overlapped both in the male and female groups of 3 months and 6 months for further analysis. Finally, we identified a novel lncRNA–miRNA–mRNA network related to adipocyte deposition using Cytoscape. In summary, this study systematically identified and analyzed the expression profiles of lncRNAs and genes during the early stages of thymic involution, which provided valuable data reference for further exploring the roles of lncRNAs in thymic involution.
2020-11-28 | GSE162271 | GEO
Project description:METTL3 governs thymocyte development and thymic involution by regulating ferroptosis
| PRJNA1130936 | ENA
Project description:During gestation, sex hormones cause a significant thymic involution which enhances fertility. This thymic involution is rapidly corrected following parturition. As thymic epithelial cells (TECs) are responsible for the regulation of thymopoiesis, we analyzed the sequential phenotypic and transcriptomic changes in TECs during the postpartum period in order to identify mechanisms triggering postpartum thymic regeneration. In particular, we performed flow cytometry analyses and deep RNA-sequencing on purified TEC subsets at several time points before and after parturition. We report that pregnancy-induced involution is not caused by loss of TECs since their number does not change during or after pregnancy. However, during pregnancy, we observed a significant depletion of all thymocyte subsets downstream of the double-negative 1 (DN1) differentiation stage. Variations in thymocyte numbers correlated with conspicuous changes in the transcriptome of cortical TECs (cTECs). The transcriptomic changes affected predominantly cTEC expression of Foxn1, its targets and several genes that are essential for thymopoiesis. By contrast, medullary TECs (mTECs) showed very little transcriptomic changes in the early postpartum regenerative phase, but seemed to respond to the expansion of single-positive (SP) thymocytes in the late phase of regeneration. Together, these results show that postpartum thymic regeneration is orchestrated by variations in expression of a well-defined subset of cTEC genes, that occur very early after parturition.
2019-11-20 | GSE138494 | GEO
Project description:Age-related thymic involution is one of the major causes of immunosenescence, characterized by reduced production of naive T cells, leading to increased susceptibility to cancers, infections, autoimmunity and reduced vaccine efficacy. Here, we reveal that the RANK/RANKL axis is altered in the thymus during aging, which results in a decline in thymic epithelial cell (TEC) and endothelial cell (EC) function and, consequently, to thymic involution. Whereas RANKL neutralization in young mice mimics thymic involution, RANKL treatment in aged individuals restores the thymic architecture, TEC and EC functional properties, and thymic T-cell production. This cascade of events results in peripheral T cell renewal and effective anti-tumor and anti-viral immune responses. Furthermore, we provide the proof-of-concept that RANKL stimulates TEC and EC in human thymic organo-cultures. Collectively, our findings identify RANKL administration as a potent therapeutic strategy to rejuvenate thymic function and improve T-cell immune function in the elderly.
2024-09-30 | GSE241880 | GEO