Chromatin assembly factor 1B critically controls early development but not functional acquisition of iNKT cells [RNA-seq]
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PROVIDER: PRJNA627600 | ENA |
REPOSITORIES: ENA
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Project description:Chromatin assembly factor 1B critically controls early development but not functional acquisition of iNKT cells
| PRJNA627593 | ENA
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 [ATAC-seq]
| PRJNA627601 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2021-05-21 | GSE149177 | GEO
Project description:The maintenance of tissue homeostasis is critically dependent on the function of tissue-resident lymphocytes, including lipid-reactive invariant natural killer T (iNKT) cells. iNKT cells have unique properties according to their tissues of residency, but if and how the tissue environment shapes their antigen specificity remains unknown. By analysing iNKT cells from tissues of mice and humans we demonstrate that their T cell receptor (TCR) repertoire is highly diverse and is distinct for iNKT cells resident in individual tissues resulting in differential lipid-antigen recognition. Within peripheral tissues, the TCR repertoire of iNKT cell recent thymic emigrants is different from that of mature cells, indicating that the iNKT population is shaped after their arrival to the tissues. Accordingly, in homeostatic conditions the repertoire of iNKT cells is modulated by tissue-specific signals that control iNKT cell activation and proliferation resulting in differential clonal expansion found for cells resident in various organs. Moreover, the iNKT cell TCR repertoire changes in response to lipid immunization and is shaped by age and by environmental changes. Thus, post-thymic modification of the iNKT cell TCR repertoire underpins the distinct antigen specificity of iNKT cells residing in peripheral tissues
2019-12-17 | GSE131420 | GEO
Project description:Transcriptional profiling of iNKT gene expression in Map3k1 control and mutant mice
2016-06-01 | E-MTAB-1561 | biostudies-arrayexpress
Project description:iNKT cells are a T lymphocyte subset displaying an innate effector phenotype that is acquired through a thymic developmental program controlled by microRNAs (miRNAs). iNKT cells lacking all miRNAs by the deletion of Dicer (Dicer KO) are markedly reduced and display a complete maturation block. In this study, we sought to gain insight into the miRNA-regulated genetic program required for iNKT cell development. By systemic analysis, we identified transcripts differentially expressed between thymic WT or Dicer KO iNKT cells and targeted by the iNKT cell-specific miRNAs. TGF-βRII, a molecule critically implicated in iNKT cell maturation, was found upregulated in Dicer KO iNKT cells together with increased TGF-β-dependent signaling. miRNAs belonging to the paralog miR-106a~363, miR-106b~25 and miR-17~92 clusters were predicted to target TGF-βRII mRNA during iNKT cell development. Thymic iNKT cells lacking all three miRNA clusters displayed both increased TGF-βRII expression and signaling and a maturation block, recapitulating those found in Dicer KO iNKT cells. Consistently, inhibition of TGF-β-dependent signaling in the absence of miRNAs, by crossing TGF-βRII KO and Dicer KO mice, rescued iNKT cell maturation. Collectively, our results highlight a fundamental requirement of the modulation of TGF-β-dependent signaling by miRNAs for iNKT cell development
2016-11-17 | GSE79901 | GEO
Project description:CD1d expression by thymocytes is required to select iNKT cells. When CD1d is expressed only on thymocytes (pLck-CD1d tg mice), iNKT cells are hyperresponsive to antigen stimulation suggesting that, in physiological conditions, these cells undergo functional education mediated by additional CD1d-expressing cells. Here, we investigated the mechanisms of this functional education. We find that peripheral iNKT cells from pLck-CD1d tg mice express significantly less SHP-1, a tyrosine phosphatase negatively regulating TCR signaling, than WT cells. iNKT cells from heterozygous SHP-1-mutated motheaten mice, displaying similar SHP-1 reduction as pLck-CD1d tg iNKT cells, are antigen-hyperresponsive. Restoring normal CD1d expression in pLck-CD1d tg mice normalizes SHP-1 expression and responsiveness of iNKT cells. In WT mice, iNKT cells upregulate SHP-1 and decrease responsiveness upon emigration from thymus to periphery. This depends on contacts with CD1d-expressing DCs. iNKT cell functional education is therefore controlled by DCs via tuning SHP-1 expression level in the periphery. Hepatic iNKT cells from wild-type and transgenic mice (expressing hCD1d molecule under the pLck promoter)
2013-03-01 | E-GEOD-42835 | biostudies-arrayexpress
Project description:Deletion of Uhrf1 resulted in stage 1-specific defects during iNKT cell development. To investigate the molecular mechanism, we sorted WT and Uhrf1-KO stage 1 iNKT cells and performed RNA-seq. By comparing gene expression profile, we found metabolic defects in Uhrf1-KO stage 1 iNKT cells. The expression of CD71 (Tfrc), two subunits of CD98 (Slc3a2 and Slc7a5) and Glut3 (Slc2a3) was reduced in stage 1 iNKT cells. Besides, the downstream pathways of AKT-mTOR axis were significantly reduced. Collectively, our results suggest that Uhrf1 is required for iNKT cell development by regulating the Akt-mTOR signaling pathway. We first sorted WT and Uhrf1-KO stage 1 iNKT cells, extracted the mRNA and performed RNA-seq. We then analyzed the differentially expressed genes and performed KEGG pathway analysis. We used RT-PCR to verify the expression of the key nutrient related genes (Tfrc, Slc3a2, Slc7a5 and Slc2a3) and used flow cytometry to test the protein level of metabolic related molecules. Besides, we also analyzed the expression of genes of mTOR downstream pathways to demonstrate that Uhrf1 mediated AKt-mTOR axis regulates iNKT cell development.
2016-03-10 | E-GEOD-77941 | biostudies-arrayexpress