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Transcriptional Regulation by NFATc1 during murine thymocyte development [ChIP-seq]

ABSTRACT: In thymus hematopoietic precursor cells differentiate into αβ T cells, γδ T cells, mucosa-associated invariant T cells (MAIT), and natural killer T (NKT) cells. We show that both ablation of NFATc1 or its induction during the DN stages of thymocyte development leads to an almost normal thymocyte development but a marked increase in γδ T cells. The γδ cells deficient for NFATc1 acquire an NKT γδ cell phenotype that exhibits the expression of CD4 co-receptor, the NK1.1 marker, the augmented usage of the Vγ1.1 and Vδ6.3 segments, and an increased in IL4 and IFN-γ production.

ORGANISM(S): Mus musculus

PROVIDER: GSE198028 | GEO | 2023/02/28

REPOSITORIES: GEO

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Transcriptional Regulation by NFATc1 during murine thymocyte development [gammadelta_T_cells RNA-seq]

Project description:In thymus hematopoietic precursor cells differentiate into αβ T cells, γδ T cells, mucosa-associated invariant T cells (MAIT), and natural killer T (NKT) cells. We show that both ablation of NFATc1 or its induction during the DN stages of thymocyte development leads to an almost normal thymocyte development but a marked increase in γδ T cells. The γδ cells deficient for NFATc1 acquire an NKT γδ cell phenotype that exhibits the expression of CD4 co-receptor, the NK1.1 marker, the augmented usage of the Vγ1.1 and Vδ6.3 segments, and an increased in IL4 and IFN-γ production.

2023-02-28 | GSE198030 | GEO

Transcriptional Regulation by NFATc1 during murine thymocyte development [BirA RNA-seq]

2023-02-28 | GSE198029 | GEO

A threshold level of NFATc1 activity is critical for thymocyte differentiation and to prevent leukemia development

Project description:NFATc1 plays a critical role in double-negative thymocyte survival and differentiation. However, the signals that regulate Nfatc1 expression are unknown. Here we show a developmental stage-specific differential expression pattern of Nfatc1 driven by the distal (P1) or proximal (P2) promoters in thymocytes. Whereas, preTCR-negative thymocytes exhibited only P2 promoter-derived Nfatc1b expression, preTCR-positive thymocytes expressed both Nfatc1b and P1 promoter-derived Nfatc1a transcripts. Inducing NFATc1a activity from P1 promoter in preTCR-negative thymocytes, in addition to the NFATc1a from P2 promoter impaired thymocyte development resulting in severe T cell lymphopenia. Additionally, we show that NFATc1 activity suppressed the B-lineage potential of immature thymocytes, and consolidated their differentiation to T cells. Further, in the pTCR-positive DN3 cells, a threshold level of NFATc1 activity was vital in facilitating T cell differentiation and to prevent T-acute lymphoblastic leukemia (T-ALL) development. Altogether, our results show NFATc1 activity is crucial in determining the T cell fate of thymocytes.

2016-04-20 | GSE80138 | GEO

TCR signal strength controls thymic differentiation of discrete proinflammatory γδT cell subsetsistinct TCR signal strength requirements in the thymus

Project description:The murine thymus produces discrete γδ T cell subsets making either IFN-γ or IL-17, but the role of the TCR in this developmental process remains controversial. Here we generated a non-transgenic and polyclonal model of reduced TCR expression and signal strength selectively on γδ T cells. Mice haploinsufficient for both CD3γ and CD3δ (CD3DH) showed normal αβ thymocyte subsets but specific defects in γδ T cell development, namely impaired differentiation of IL-17-producing embryonic Vγ6+ (but not adult Vγ4+) γδ T cells and a marked depletion of IFN-γ-producing CD122+ NK1.1+ (Vγ1-biased) γδ T cells throughout life. As result, adult CD3DH mice showed defective peripheral IFN-γ responses and were resistant to experimental cerebral malaria. Thus, strong TCR signaling is required within specific developmental windows with distinct Vγ usage and differential cytokine production by effector γδ T cell subsets.

2016-03-29 | GSE71637 | 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

Microarray expression profiling of NKT and MAIT subsets in different organs of B6-MAIT/CAST mice.

Project description:MAIT cells (MAITs) represent an abundant T lymphocyte subset with unique specificity for microbial metabolites presented by the MHC-1b molecule, MR1. MAIT conservation along evolution indicates important, non-redundant functions, but their low frequency in mice has hampered their detailed characterization. Here, we performed a transcriptomic analysis of murine MAITs in comparison with NKT subsets and with mainstream T cells in spleen and peripheral organs of B6-MAIT/CAST mice expressing a Rorc-GFP transgene. MAIT and NKT cells have been FACS-sorted after tetramer staining (MR1:5-OP-RU Tet+ for MAIT, CD1d:PBS57Tet+ for NKT), and 1/17 subsetting based on the expression of Rorc.

2018-12-03 | E-MTAB-7133 | biostudies-arrayexpress

γδ-T cells and αβ-TCR transduced γδ-T cells

Project description:RNA expression of unstimulated γδ-T cells,γδ-TCR-stimulated γδ-T cells, unstimulated αβ-TCR transduced γδ-T cells and αβ-TCR-stimulated αβ-TCR transduced γδ-T cells.

2023-09-07 | GSE216880 | GEO

Metabolic signaling directs the reciprocal lineage decisions of αβ and γδ T cells

Project description:The interaction between extrinsic factors and intrinsic signal strength governs thymocyte development, but mechanisms linking them remain elusive. We report that mTORC1 couples microenvironmental cues with metabolic programs in orchestrating reciprocal development of two fundamentally distinct lineages, αβ and γδ T cells. Loss of mTORC1 impairs αβ but promotes γδ T cell development, and disrupts metabolic remodeling of oxidative and glycolytic metabolism. Mechanistically, reactive oxygen species (ROS) controlled by mTORC1 serves as a key metabolic signal, and perturbation of redox homeostasis impinges upon fate decisions. Furthermore, singlecell RNA sequencing and genetic dissection reveal that mTORC1 links developmental signals from T cell receptors and NOTCH to coordinate metabolic activity and signal strength. Our results establish mTORC1-driven metabolic signaling as a fundamental mechanism underlying thymocyte lineage choices. We used microarrays to compare the global transcription profiles of WT and Raptor-null cell populations in DN3a developing thymocytes, immaturesingle-positive (ISP) T-cells, and γδ T-cells

2018-07-06 | GSE86495 | GEO

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

DNA METHYLATION DURING αβ T CELL DEVELOPMENT IN THE HUMAN THYMUS [methylation]

Project description:Thymocyte differentiation is a complex process which involves well-defined sequential developmental stages that finally result in the generation of mature αβ and γδ T cells. Here, we analyzed DNA methylation and gene expression profiles at successive human thymus developmental stages from early T-cell progenitors to single positive (SP) CD4+ and CD8+ subpopulations

2014-12-30 | GSE55111 | GEO

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