Similar Datasets
Project description:T cell development is a complicatedly hierarchical process which is closely related with the chromatin activation and gene transcription. CD4+CD8+ double-positive (DP) thymocytes give rise to both conventional TCRαβ+ T cells and natural killer T cells, but they display different characteristics. Compared with conventional TCRαβ+ T cells, invariant natural killer T cells (iNKT cells) as the major population of NKT cells, are CD1d-restricted, recognize glycolipid antigens and rapidly exert effector functions after stimulation. However, the specific molecular mechanism of early iNKT cell development remain incompletely understood. Here the authors show that deletion of Chromatin assembly factor 1B (CHAF1b) remains the normal development of conventional TCRαβ+ T cell, but specifically impacts iNKT cell generation and completely impairs iNKT cell development from stage 0 with a PLZF independent way. This dysregulation is accompanied by a specific decrease in gene transcription of Vα14-Jα18, an impairment in TCR signaling and PLZF expression. Notably, ectopic expression of a transgenic Vα14-Jα18 TCR completely rescues these defects in Chaf1b-deficient iNKT cells. Moreover, cytokine secretion and anti-tumor activity are substantially maintained in Chaf1b-deficient iNKT cells with transgenic Vα14-Jα18 TCR. Our study identifies CHAF1b as a distinct regulator controls early development of iNKT cells via transcriptional regulation of Vα14-Jα18.
2021-05-21 | GSE149176 | GEO
Project description:T cell development is a complicatedly hierarchical process which is closely related with the chromatin activation and gene transcription. CD4+CD8+ double-positive (DP) thymocytes give rise to both conventional TCRαβ+ T cells and natural killer T cells, but they display different characteristics. Compared with conventional TCRαβ+ T cells, invariant natural killer T cells (iNKT cells) as the major population of NKT cells, are CD1d-restricted, recognize glycolipid antigens and rapidly exert effector functions after stimulation. However, the specific molecular mechanism of early iNKT cell development remain incompletely understood. Here the authors show that deletion of Chromatin assembly factor 1B (CHAF1b) remains the normal development of conventional TCRαβ+ T cell, but specifically impacts iNKT cell generation and completely impairs iNKT cell development from stage 0 with a PLZF independent way. This dysregulation is accompanied by a specific decrease in gene transcription of Vα14-Jα18, an impairment in TCR signaling and PLZF expression. Notably, ectopic expression of a transgenic Vα14-Jα18 TCR completely rescues these defects in Chaf1b-deficient iNKT cells. Moreover, cytokine secretion and anti-tumor activity are substantially maintained in Chaf1b-deficient iNKT cells with transgenic Vα14-Jα18 TCR. Our study identifies CHAF1b as a distinct regulator controls early development of iNKT cells via transcriptional regulation of Vα14-Jα18.
2021-05-21 | GSE149174 | GEO
Project description:Chromatin assembly factor 1B critically controls early development but not functional acquisition of iNKT cells
| PRJNA627593 | ENA
Project description:Chromatin assembly factor 1B critically controls early development but not functional acquisition of iNKT cells [RNA-seq]
| PRJNA627600 | ENA
Project description:Chromatin assembly factor 1B critically controls early development but not functional acquisition of iNKT cells [ATAC-seq]
| PRJNA627601 | ENA
Project description:Invariant natural killer T (iNKT) cells develop from CD4+CD8+ double-positive (DP) thymocytes and express an invariant V?14-J?18 T-cell receptor (TCR) ?-chain. Generation of these cells requires the prolonged survival of DP thymocytes to allow for V?14-J?18 gene rearrangements and strong TCR signaling to induce the expression of the iNKT lineage-specific transcription factor PLZF. Here, we report that the transcription factor Yin Yang 1 (YY1) is essential for iNKT cell formation. Thymocytes lacking YY1 displayed a block in iNKT cell development at the earliest progenitor stage. YY1-deficient thymocytes underwent normal V?14-J?18 gene rearrangements, but exhibited impaired cell survival. Deletion of the apoptotic protein BIM failed to rescue the defect in iNKT cell generation. Chromatin immunoprecipitation and deep-sequencing experiments demonstrated that YY1 directly binds and activates the promoter of the Plzf gene. Thus, YY1 plays essential roles in iNKT cell development by coordinately regulating cell survival and PLZF expression.
| S-EPMC6804577 | biostudies-literature
Project description:Innate T cells, including invariant natural killer T (iNKT) and mucosal-associated innate T (MAIT) cells, are a heterogeneous T lymphocyte population with effector properties preprogrammed during their thymic differentiation. How this program is initiated is currently unclear. Here, we show that the transcription factor BCL-6 was transiently expressed in iNKT cells upon exit from positive selection and was required for their proper development beyond stage 0. Notably, development of MAIT cells was also impaired in the absence of Bcl6. BCL-6-deficient iNKT cells had reduced expression of genes that were associated with the innate T cell lineage, including Zbtb16, which encodes PLZF, and PLZF-targeted genes. BCL-6 contributed to a chromatin accessibility landscape that was permissive for the expression of development-related genes and inhibitory for genes associated with naive T cell programs. Our results revealed new functions for BCL-6 and illuminated how this transcription factor controls early iNKT cell development.
| S-EPMC7442690 | biostudies-literature
Project description:Macrophages play an important role in immunity and homeostasis. Upon pathogen recognition via specific receptors, they rapidly induce inflammatory responses. This process is tightly controlled at the transcriptional level. The DNA binding zinc-finger protein CCCTC-binding factor (Ctcf) is a crucial regulator of long-range chromatin interactions and coordinates specific communication between transcription factors and gene expression processes. In this study, the Ctcf gene was specifically deleted in myeloid cells by making use of the transgenic Cre-LoxP system. Conditional deletion of the Ctcf gene in myeloid cells induced a mild phenotype in vivo. Ctcf-deficient mice exhibited significantly reduced expression of major histocompatibility complex (MHC) class II in the liver. Ctcf-deficient macrophages demonstrated a normal surface phenotype and phagocytosis capacity. Upon Toll-like receptor (TLR) stimulation, they produced normal levels of the pro-inflammatory cytokines IL-12 and IL-6, but manifested a strongly impaired capacity to produce tumor-necrosis factor (TNF) and IL-10, as well as to express the IL-10 family members IL-19, IL-20 and IL-24. Taken together, our data demonstrate a role of Ctcf that involves fine-tuning of macrophage function.
| S-EPMC4002140 | biostudies-literature
Project description:Invariant natural killer T (iNKT) cells are activated during infection, but how they limit microbial growth is unknown in most cases. We investigated how iNKT cells suppress intracellular Mycobacterium tuberculosis (Mtb) replication. When co-cultured with infected macrophages, iNKT cell activation, as measured by CD25 upregulation and IFN? production, was primarily driven by IL-12 and IL-18. In contrast, iNKT cell control of Mtb growth was CD1d-dependent, and did not require IL-12, IL-18, or IFN?. This demonstrated that conventional activation markers did not correlate with iNKT cell effector function during Mtb infection. iNKT cell control of Mtb replication was also independent of TNF and cell-mediated cytotoxicity. By dissociating cytokine-driven activation and CD1d-restricted effector function, we uncovered a novel mediator of iNKT cell antimicrobial activity: GM-CSF. iNKT cells produced GM-CSF in vitro and in vivo in a CD1d-dependent manner during Mtb infection, and GM-CSF was both necessary and sufficient to control Mtb growth. Here, we have identified GM-CSF production as a novel iNKT cell antimicrobial effector function and uncovered a potential role for GM-CSF in T cell immunity against Mtb.
| S-EPMC3879349 | biostudies-literature
Project description:Invariant NKT (iNKT) cell functional subsets are defined by key transcription factors and output of cytokines, such as IL-4, IFN-?, IL-17, and IL-10. To examine how TCR specificity determines iNKT function, we used somatic cell nuclear transfer to generate three lines of mice cloned from iNKT nuclei. Each line uses the invariant V?14J?18 TCR? paired with unique V?7 or V?8.2 subunits. We examined tissue homing, expression of PLZF, T-bet, and ROR?t, and cytokine profiles and found that, although monoclonal iNKT cells differentiated into all functional subsets, the NKT17 lineage was reduced or expanded depending on the TCR expressed. We examined iNKT thymic development in limited-dilution bone marrow chimeras and show that higher TCR avidity correlates with higher PLZF and reduced T-bet expression. iNKT functional subsets showed distinct tissue distribution patterns. Although each individual monoclonal TCR showed an inherent subset distribution preference that was evident across all tissues examined, the iNKT cytokine profile differed more by tissue of origin than by TCR specificity.
| S-EPMC5518629 | biostudies-literature