Essential functions for ID proteins at multiple checkpoints in natural killer T cell development
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE50933 | GEO | 2013/11/19
SECONDARY ACCESSION(S): PRJNA219391
REPOSITORIES: GEO
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Project description:Thymic iNKT cell development is divided into four stages (stage 0-3) that are characterised, in C57BL/6 mouse strain, by the differential expression of surface markers, such as CD24, CD44 and NK1.1. During transition from immature to mature iNKT cell subsets, gene expression is tightly regulated. Here, we used microarray analysis to detail the influence of the transcriptional regulator ID3 during iNKT cell maturation in the thymus. Stage 1 (Tet+CD24-CD44-NK1.1-) and Stage 2 (Tet+CD24-CD44+NK1.1-) iNKT cells from WT and Id3KO thymi were FACS sorted for RNA extraction and Affymetrix hybridisation.
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2015-12-31 | E-GEOD-53150 | biostudies-arrayexpress
Project description:We used whole genome transcriptome as gene discovery to further understand the differential behaviour of the first (embryonic) and second waves of thymic settling progenitors in the murine embryo. Mouse embryos at days 13 and 18 of gestation were isolated and the thymic lobes were dissected. Single cell suspension was prepared and treated with biotinilated antibodies to CD3, CD4, CD8, TER119, Gr1, CD25, CD19, NK1.1 and CD11c. Cell suspensions were then incubated with streptavidin Miltenyi Macs beads. Lineage negative thymocytes were recovered in Macs columns. Cell suspensions were then incubated with antibodies against CD135, CD117, CD44, CD24 and Streptavidin bound to PECy7. Lin-, CD117+, CD44+, CD24low, CD135+ cells were then isolated by cell sorting. 3 biological replicates of each sample were isolated with 104-3x104 cells
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Project description:The indicated thymic progenitor population was sorted via FACS and then loaded into a Fluidigm C1 small cell capture chip for single-cell capture, lysis, reverse transcription, and preamplification. Preamplified products were analyzed on a BioMark HD with EvaGreen chemistry. The genes analyzed were selected based on bulk RNA sequencing data and/or prior publications, including genes relevant for gamma/delta T cells and T cell progenitors. B6=C57BL/6J, Rag=B6.Rag1-/-, Tcrd=B6.Tcrd-/-, DN1d=Live/TCRd-/Lin-/CD44+/CD25-/CD24+/cKit-, DN2=Live/TCRd-/Lin-/CD44+/CD25+/cKit+, cKit-=Live/TCRd-/Lin-/CD44+/CD25-/cKit-. Lin=CD3/CD8/CD11b/CD11c/CD19/Gr-1/NK1.1/TCRb/Ter-119 Sample naming nomenclature is as follows: MouseLine_CellPopoulation_DateCaptured_CaptureChamber_CellNumberInChamber
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Project description:Id proteins have been shown to promote the differentiation of conventional αβ and γδT cells, and to suppress the expansion of invariant Natural Killer T (iNKT) cells and innate-like γδNKT within their respective cell lineages. However, it remains to be determined whether Id proteins regulate lineage specification in developing T cells that give rise to these distinct cell fates. Here we report that in the absence of Id2 and Id3 proteins, E2A prematurely activates genes critical for the iNKT cell lineage prior to TCR expression. Lack of Id proteins also promotes a biased TCR rearrangement in favor of iNKT cell fate prior to selection at the CD4+CD8+ double positive (DP) stage. Enhanced iNKT development in Id3-deficient mice lacking γδNKT cells suggests that Id3 regulates the lineage competition between these populations. RNA-Seq analysis establishes E2A as the transcriptional regulator of both iNKT and γδNKT development. In the absence of pre-TCR signaling, Id2/Id3 deletion gives rise to a large population of iNKT cells and a unique innate-like DP population, despite the block in conventional αβ T cell development. The transcriptional profile of these unique DP cells reflects enrichment of innate-like signature genes, including PLZF (Zbtb16) and Granzyme A (Gzma). Results from these genetic models and genome-wide analyses suggest that Id proteins suppress E2A-driven innate-like T cell programs prior to TCR selection to enforce predominance of conventional T cells.
2018-01-23 | GSE89847 | GEO
Project description:Id proteins have been shown to promote the differentiation of conventional αβ and γδT cells, and to suppress the expansion of invariant Natural Killer T (iNKT) cells and innate-like γδNKT within their respective cell lineages. However, it remains to be determined whether Id proteins regulate lineage specification in developing T cells that give rise to these distinct cell fates. Here we report that in the absence of Id2 and Id3 proteins, E2A prematurely activates genes critical for the iNKT cell lineage prior to TCR expression. Lack of Id proteins also promotes a biased TCR rearrangement in favor of iNKT cell fate prior to selection at the CD4+CD8+ double positive (DP) stage. Enhanced iNKT development in Id3-deficient mice lacking γδNKT cells suggests that Id3 regulates the lineage competition between these populations. RNA-Seq analysis establishes E2A as the transcriptional regulator of both iNKT and γδNKT development. In the absence of pre-TCR signaling, Id2/Id3 deletion gives rise to a large population of iNKT cells and a unique innate-like DP population, despite the block in conventional αβ T cell development. The transcriptional profile of these unique DP cells reflects enrichment of innate-like signature genes, including PLZF (Zbtb16) and Granzyme A (Gzma). Results from these genetic models and genome-wide analyses suggest that Id proteins suppress E2A-driven innate-like T cell programs prior to TCR selection to enforce predominance of conventional T cells.
2018-01-23 | GSE100601 | GEO
Project description:Id proteins have been shown to promote the differentiation of conventional αβ and γδT cells, and to suppress the expansion of invariant Natural Killer T (iNKT) cells and innate-like γδNKT within their respective cell lineages. However, it remains to be determined whether Id proteins regulate lineage specification in developing T cells that give rise to these distinct cell fates. Here we report that in the absence of Id2 and Id3 proteins, E2A prematurely activates genes critical for the iNKT cell lineage prior to TCR expression. Lack of Id proteins also promotes a biased TCR rearrangement in favor of iNKT cell fate prior to selection at the CD4+CD8+ double positive (DP) stage. Enhanced iNKT development in Id3-deficient mice lacking γδNKT cells suggests that Id3 regulates the lineage competition between these populations. RNA-Seq analysis establishes E2A as the transcriptional regulator of both iNKT and γδNKT development. In the absence of pre-TCR signaling, Id2/Id3 deletion gives rise to a large population of iNKT cells and a unique innate-like DP population, despite the block in conventional αβ T cell development. The transcriptional profile of these unique DP cells reflects enrichment of innate-like signature genes, including PLZF (Zbtb16) and Granzyme A (Gzma). Results from these genetic models and genome-wide analyses suggest that Id proteins suppress E2A-driven innate-like T cell programs prior to TCR selection to enforce predominance of conventional T cells.
2018-01-23 | GSE89848 | GEO
Project description:Invariant natural killer T (iNKT) cells are a rare but heterogenous T-cell subset with potent cytotoxic and immunomodulatory properties. During thymic development, murine iNKT cells go through different maturation stages and differentiate into distinct sublineages, namely iNKT1, iNKT2, and iNKT17 cells. Recent reports indicate that iNKT2 cells display immature properties and also give rise to other subsets, whereas iNKT1 cells seem to be terminally differentiated. Whether human iNKT cells follow a similar differentiation model is still unknown. To define the maturation stages and to assess the sublineage commitment of human iNKT cells during thymic development, in the present study we performed single-cell RNA sequencing analysis on human iNKT cells isolated from thymocytes. We show that human iNKT cells displayed heterogeneity and our unsupervised analysis identified two clusters: a first cluster expressed an immature profile with high expression of genes that are important for iNKT cell development and proliferation, whereas a second cluster displayed a mature, terminally differentiated profile. Trajectory analysis suggested an ontological relationship between the two clusters. Evaluation of the expression of sublineage-defining gene sets revealed that the first cluster contained mainly cells with an iNKT2 signature, whereas the more differentiated one contained cells that resembled murine iNKT1 cells. Our data point to the existence of different maturation stages of human thymic iNKT cells and provide evidence for sublineage commitment of iNKT cells in the human thymus.
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Project description:Invariant natural killer T cells (iNKT) expressing the retinoic acid receptor-related orphan receptor γt (RORγt) and producing IL-17 represent a minor subset of CD1d-restricted iNKT cells (iNKT17) in C57BL/6J (B6) mice. We aimed in this study to define the reasons for their low distribution and the sequence of events accompanying their normal thymic development. We found that RORγt+ iNKT cells have higher proliferation potential and a greater propensity to apoptosis than RORγt- iNKT cells. These cells do not likely reside in the thymus indicating that thymus emigration, and higher apoptosis potential, could contribute to RORγt+ iNKT cell reduced thymic distribution. Ontogeny studies suggest that mature HSAlow RORγt+ iNKT cells might develop through developmental stages defined by a differential expression of CCR6 and CD138 during which RORγt expression and IL-17 production capabilities are progressively acquired. Finally, we found that RORγt+ iNKT cells perceive a strong TCR signal that could contribute to their entry into a specific Th17 like developmental program influencing their survival and migration. Overall, our study proposes a hypothetical thymic developmental sequence for iNKT17 cells, which could be of great use to study molecular mechanisms regulating this developmental program.
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Project description:We identified a novel subset of iNKT cells, C2 iNKT cells, that circulate in the periphery. Correspondingly, we characterized the tissue-resident iNKT cell subset, C1 iNKT cells. The development and terminal maturation of C2 iNKT cells completely depended on the thymic epithelial IL-15 niche, whereas C1 iNKT cells were regulated also by local IL-15 niches in peripheral tissues. C2 iNKT cells expressed high levels of genes related to cytotoxicity and exhibited more NK cell-like features. Functionally, C2 iNKT cells regulated self-antigen expression for immune tolerance in the thymus and mediated cancer immunosurveillance in the periphery.
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