Mapping the thymic hematopoietic antigen presenting cell network
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE291388 | GEO | 2025/09/29
REPOSITORIES: GEO
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Project description:Thymic antigen-presenting cells (APCs), including thymic dendritic cells (t-DCs) and medullary thymic epithelial cells (mTECs) have been described to play a critical role in thymic Treg generation. Our findings could show that both these thymic APCs can induce a more pronounced demethylation of Foxp3 and other Treg-specific epigenetic signature genes in developing Tregs when compared to splenic DCs. In order to elucidate the unique properties of thymic APCs, gene expression profiling was performed in comparison to splenic DCs. Transcriptome analysis of thymic APCs revealed differential expression of costimulatory molecules that could be involved in stable Treg generation. Importantly, both mTEC- and t-DC- induced alloantigen-specific Tregs displayed significantly higher efficacy in prolonging skin allograft acceptance when compared to alloantigen-specific Tregs generated by splenic DCs.
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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.
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Project description:Thymic epithelial cells (TECs) govern thymic T lymphocyte differentiation and selection. They can be divided into cortical and medullary TECs based on their anatomical location, function and molecular features. Cortical TECs (cTECs) provide the microenvironment for the commitment of haematopoietic precursors to the T lymphoid lineage and mediate the positive selection of CD4+CD8+ double-positive thymocytes. Medullary TECs (mTECs) facilitate the negative selection of self-reactive thymocytes and the differentiation of FOXP3+ regulatory T (Treg) cells2. Medullary TECs are also distinctive for their "promiscuous" gene expression, transcribing thousands of peripheral tissue genes (PTG) that are otherwise only expressed highly in one or two other organs. Much of this PTG expression by mTECs is controlled by the autoimmune regulator, AIRE. To determine the transcriptional impact of Kat7 loss, we purified mTECs and cTECs from Kat7-knockout and control mice and performed RNA-seq. The mTECs were further divided into MHCII-high and MHCII-low subsets.
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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.
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Project description:To examine the role of key immune populations within the thymic stroma in interferon production, we conducted bulk RNA-sequencing on postnatal thymic epithelial cells, B cells, thymocytes, plasmacytoid dendritic cells, and myeloid dendritic cells.
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Project description:The decline in adaptive immunity, naïve T-cell output and a contraction in the peripheral T cell receptor (TCR) repertoire with age are largely attributable to thymic involution and the loss of critical cytokines and hormones within the thymic microenvironment. To assess the molecular changes associated with this loss of thymic function, we used cDNA microarray analyses to examine the transcriptomes of thymocytes from mice of various ages ranging from very young (1 month) to very old (24 months). Genes associated with various biological and molecular processes including oxidative phosphorylation, T- and B- cell receptor signaling and antigen presentation were observed to significantly change with thymocyte age. These include several immunoglobulin chains, chemokine and ribosomal proteins, annexin A2, vav 1 and several S100 signaling proteins. The increased expression of immunoglobulin genes in aged thymocytes could be attributed to the thymic B cells which were found to be actively producing IgG and IgM antibodies. Upon further examination, we found that purified thymic T cells derived from aged but not young thymi also exhibited IgM on their cell surface suggesting the possible presence of auto-antibodies on the surface thymocytes with advancing age. These studies provide valuable insight into the cellular and molecular mechanisms associated with thymic aging. Keywords: Thymocytes, thymic involution, aging, time course
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Project description:We report the identification of immature thymic CD4(-),CD8(-) double-negative (DN)1e cells with the NKT cell lineage potential. We also analyzed the gene expression profiles of DN1e thymocytes compared with those of mature thymic NKT cell developmental stages termed NKT stage-1, 2, and -3, which are characterized by differential expression levels of NK1.1 and CD44 antigens in C57BL/6 mouse strain. Next generation sequencing of total transcriptomes using total RNA isolated from FACS sorted ex vivo thymic DN1eP (Lin-/CD44+/CD25-/CD24low/CD5+/CD27+/Ly108-/CXCR3+) fraction, and mature thymic alphaGalCer-loaded CD1d dimer+TCRbeta+ NKT cell developmental stage-1 (CD44-/NK1.1-), stage-2 (CD44+/NK1.1-), and stage-3 (CD44+/NK1.1+) cells.
2015-12-31 | E-GEOD-53150 | biostudies-arrayexpress
Project description:We report the identification of immature thymic CD4(-),CD8(-) double-negative (DN)1e cells with the NKT cell lineage potential. We also analyzed the gene expression profiles of DN1e thymocytes compared with those of mature thymic NKT cell developmental stages termed NKT stage-1, 2, and -3, which are characterized by differential expression levels of NK1.1 and CD44 antigens in C57BL/6J mouse strain.
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