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Krüppel-like factor 4 regulates T cell function

ABSTRACT: Krüppel-like factor 4 (Klf4), a transcription factor mediating context-dependent activation or repression, plays a key role in maintaining pluripotency of stem cells and in regulating cell differentiation. However, the precise function of Klf4 in T cell development and differentiation is largely unknown. Here we showed that Klf4 was highly expressed in thymocyte subsets and mature T cells, and was rapidly down-regulated in mature T cells after activation. In T cell-specific Klf4 conditional knockout mice, we observed a modest reduction of thymocytes (27%). This was due partly to the loss of Klf4 repression of Cdkn1b expression in thymocytes resulting in decreased proliferation of DN thymocytes. Together, these findings identify Klf4 as a critical regulator in T cell development.

ORGANISM(S): Mus musculus

PROVIDER: GSE24880 | GEO | 2011/06/24

SECONDARY ACCESSION(S): PRJNA132021

REPOSITORIES: GEO

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Krüppel-like factor 4 regulates T cell function

Project description:Krüppel-like factor 4 (Klf4), a transcription factor mediating context-dependent activation or repression, plays a key role in maintaining pluripotency of stem cells and in regulating cell differentiation. However, the precise function of Klf4 in T cell development and differentiation is largely unknown. Here we showed that Klf4 was highly expressed in thymocyte subsets and mature T cells, and was rapidly down-regulated in mature T cells after activation. In T cell-specific Klf4 conditional knockout mice, we observed a modest reduction of thymocytes (27%). This was due partly to the loss of Klf4 repression of Cdkn1b expression in thymocytes resulting in decreased proliferation of DN thymocytes. Together, these findings identify Klf4 as a critical regulator in T cell development. Klf4fl/fl mice (Katz et al., 2002) were crossed with CD4-Cre mice (Lee et al., 2001) to generate Klf4fl/fl-CD4-Cre+ (Klf4 conditional knockout in T cells) and Klf4fl/fl-CD4-Cre- (control) mice. Mice used for experiments were between 8 and 10 weeks old. Total RNA was extracted from freshly isolated DP+SP4 thymocytes from 3 KO mice and 3 control mice. RNA samples were labeled and hybridized to Illumina Sentrix MouseRef-8 v2 bead arrays.

2011-06-24 | E-GEOD-24880 | biostudies-arrayexpress

Tissue-specific changes in Tcrb conformation

Project description:We report the changes in Tcrb interactome upon transitioning from DN to DP stage of thymocyte development Examination of the interactomes of Eb and Trbv5 viewpoints in RAG-deficient DN and DP thymocytes

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Role of AhR in thymocyte emigration in vivo

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Transcription profiling of mouse double negative thymocytes

Project description:In order to understand the molecular mechanisms of DN thymocyte development, it may be also of use to clarify how these developmental processes are regulated in terms of their entire gene expression, to which cell differentiation is ultimately ascribed. In the current study, we approached this issue by investigating gene expression profiles in discrete subsets of DN thymocytes under development, in which DN2, DN3, and DN4 thymocytes were sorted and subjected to expression profiling analysis with high-density oligonucleotide microarrays. Experiment Overall Design: The DN2, DN3, and DN4 populations were FACS-sorted from DN thymocytes harvested from four C57BL/6 mice and analyzed by AffymetrixÂ® Mouse Genome 430 2.0 ArrayÂ® for gene expression. Four independent experiments were performed using 16 mice.

2008-06-15 | E-GEOD-7784 | biostudies-arrayexpress

Expression profiling of double negative thymocytes

2007-05-17 | GSE7784 | GEO

scRNAseq in Pten enhancer wild-type or deleted thymocytes, enriched for immature thymocyte stages (CD4-CD3-)

Project description:Single cell suspensions of total thymocytes were obtained from Pten enhancer (PE) wild-type or knockout mice. This single-cell suspension was enriched in CD4-CD3- immature thymocyte progenitor cells. CD4-CD3- enriched thymocytes were then mixed 1:1 with single-cell suspensions from total unenriched thymocytes and subsequntly loaded in a 10x Chromium instrument for single-cell RNAseq analyses. Our results revealed Pten levels are signifcantly decreased in CD4-CD8- double negative (DN) thymocytes, CD8+ intermediate single positive (ISP) thymocytes and CD4+CD8+ double positive (DP) thymocytes in PE knockout mice, compared to PE wild-type mice.

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Notch-Induced Endoplasmic Reticulum-Associated Degradation Governs Thymocyte β Selection

Project description:β -selection imposes a considerable demand for new protein synthesis of the newly rearranged Tcrβ gene and the multiple factors that execute the transcriptional and metabolic programs demanded by DN thymocyte proliferation. However, how proteome homeostasis or “proteostasis” is regulated during thymocyte development is largely unknown. Here, we show that the endoplasmic reticulum (ER)- associated degradation (ERAD), but not the unfolded protein response (UPR), is the master regulator of physiological ER proteostasis in immature DN thymocytes. The ERAD machinery was critically required for successful β-selection of DN3 thymocytes and consequently, ERAD deficiency impeded αβ T cell development. The Sel1L-Hrd1 complex is the most conserved branch of mammalian ERAD machinery. Deletion of Sel1l impaired DN3 to DN4 thymocyte transition and severely impaired αβ T cell development. Mechanistically, Sel1l deficiency induced unresolved ER stress that triggered thymocyte apoptosis through the PERK pathway. This study revealed the stringent protein quality control through the SEL1L-ERAD pathway is required for successful b-selection and the development of the ab T cells that mediate adaptive immunity.

2021-05-07 | GSE173993 | GEO

Pre-T cell receptor Self-MHC Sampling Restricts Thymocyte Dedifferentiation

Project description:Programming T lymphocytes to distinguish self from non-self is a vital, multi-step process arising in the thymus. Signalling through the pre-T cell receptor (preTCR), a CD3-associated heterodimer comprising an invariant pTα chain and a clone-specific β chain, constitutes a critical early checkpoint in thymocyte development within the αβ T-cell lineage. Recent work demonstrates that preTCRs arrayed on double negative (DN) thymocytes, like αβ TCRs appearing on double positive (DP) thymocytes, ligate peptides bound to MHC molecules (pMHC) on thymic stroma but via a different molecular docking strategy. Here we show the consequences of those distinctive interactions for thymocyte progression, using synchronized fetal thymic progenitor cultures differing in the presence or absence of pMHC on support stroma, determining single cell transcriptomes at key thymocyte developmental transitions. Although MHC negative stroma fosters αβ T lymphocyte differentiation, the absence of pMHC-preTCR interplay leads to deviant thymocyte transcriptional programming associated with de-differentiation. Highly proliferative DN and DP subsets with antecedent characteristics of T cell lymphoblastic and myeloid malignancies emerge. Thus, in addition to fostering β chain repertoire broadening for subsequent αβ TCR utilization, preTCR-pMHC interaction limits cellular plasticity to facilitate normal thymocyte differentiation and proliferation that, if absent, introduces significant developmental vulnerabilities.

2022-10-18 | GSE186049 | GEO

Deletion of the mitochondria-shaping protein Opa1 during early thymocyte maturation impacts mature memory T cell metabolism

Project description:OPA1, a mitochondria-shaping protein controlling cristae biogenesis and respiration, is required for memory T cell function, but whether it affects intrathymic T cell development is unknown. Here we show that OPA1 is necessary for thymocyte maturation at the double negative (DN)3 stage when rearrangement of the T-cell receptor β (Tcrβ) locus occurs. By profiling mitochondrial function at different stages of thymocyte maturation, we find that DN3 cells rely on oxidative phosphorylation (OXPHOS). Consistently, Opa1 deletion during early T cell development impairs respiration of DN3 cells and reduces their number. Opa1-deficient DN3 cells indeed display stronger TCR signaling and are more prone to cell death. The surviving Opa1-/- thymocytes that reach the periphery as mature T cells display an Effector Memory phenotype even in the absence of antigenic stimulation but are unable to generate metabolically fit long-term memory T cells. Thus, mitochondrial defects early during T cell development affect mature T cell function.

2021-07-27 | GSE165579 | GEO

Role of AhR in thymocyte emigration in vivo

Project description:Over-activation of the aryl hydrocarbon receptor by TCDD in mice leads among other phenotypes to a severe thymic atrophy accompanied by immunosuppression. TCDD causes a block in thymocyte maturation and a preferential emigration of immature CD4-CD8- DN thymocytes (recent thymic emigrants) into the periphery. As part of this study gene expression profiles from DN thymocytes and thymic emigrants were generated from TCDD and solvent control mice Keywords: Affymetrix, TCDD, CD4-CD8- thymocytes, Thymus involution, thymic emigration, Ahr Female, 6-8 week old C57BL6 mice were i.p. injected with 10 M-BM-5g/kg TCDD. After 5 days mice were anesthezised and FITC injected into their thymi. after 24h mice were sacrificed and CD4-CD8-FITC+ cells isolated from thymus (thymocytes) and spleen (recent thymus emigrants).

2008-11-25 | E-GEOD-10166 | biostudies-arrayexpress

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