TCR density in early iNKT cell precursors regulates agonist selection and subset differentiation in mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE129252 | GEO | 2019/04/03
REPOSITORIES: GEO
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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:Invariant Natural Killer T (iNKT) cells are a unique subset of T lymphocytes with a memory like phenotype which express invariant T cell receptor (TCR) chain comprised of a Vα14-Jα18 rearrangement in mice. In the present study, we characterize the transcriptomes of thymic iNKT cells at the single cell level to reveal the underlying metabolic adaptation that exists over the course of iNKT cell development.
2023-12-29 | GSE248939 | GEO
Project description:TCR density in early iNKT cell precursors regulates agonist selection and subset differentiation in mice
| PRJNA530611 | ENA
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:Development of T cells is controlled by the signal strength of the TCR. The scaffold protein Kinase D-interacting substrate of 220 kDa (Kidins220) binds to the TCR; however, its role in T cell development was unknown. Here, we show that T cell-specific Kidins220 knock-out (T-KO) mice have strongly reduced invariant natural killer T (iNKT) cell numbers and modest decreases in conventional T cells. Enhanced apoptosis due to increased TCR signaling in T-KO iNKT thymocytes of developmental stage 2 and 3 shows that Kidins220 downregulates TCR signaling at these stages. scRNAseq indicated that the transcription factor Aiolos is downregulated in Kidins220-deficient iNKT cells. Analysis of an Aiolos KO demonstrated that Aiolos is a downstream effector of Kidins220 during iNKT cell development. In the periphery, T-KO iNKT cells show reduced TCR signaling upon stimulation with α-galactosylceramide, suggesting that Kidins220 promotes TCR signaling in peripheral iNKT cells. Thus, Kidins220 reduces or promotes signaling dependent on the iNKT cell developmental stage.
2024-03-11 | GSE253196 | GEO
Project description:Three major phenotypically and functionally distinct invariant Natural Killer T (iNKT) cell subsets (iNKT1, iNKT17 and iNKT2), each with propensity to traffic to different tissues and to secrete different cytokines upon activation, have been defined. These fate assignments can be conferred upon iNKT cells during development in the thymus, but the cues that direct these decisions remain unclear. Here, we show that T cell antigen receptor (TCR) signal strength governs the development of iNKT cell subsets in the thymus, with high signaling strength necessary for iNKT2 and iNKT17 development. Alteration of TCR diversity and/or signaling dramatically diminished iNKT2 and iNKT17 cell subset development in a cell intrinsic manner. Decreased TCR signaling affected the persistence of Egr2 expression and the upregulation of PLZF both in vivo and in vitro. Genome-wide chromatin accessibility analysis revealed subset-specific activity of regulatory elements associated with unique signatures of transcription factor binding sites. NFAT and Egr binding motifs were found preferentially enriched in chromatin regulatory regions specifically accessible in iNKT2 cells that were lost in iNKT2 cells that had developed with reduced TCR signaling. Altogether, these data suggest a model of iNKT cell subset development where variable TCR signaling induces changes in chromatin accessibility at NFAT and Egr binding sites which exerts a determinative influence on the dynamic of gene enhancer accessibility that affects the developmental fate of iNKT cells.
2018-05-18 | GSE111427 | GEO
Project description:Three major phenotypically and functionally distinct invariant Natural Killer T (iNKT) cell subsets (iNKT1, iNKT17 and iNKT2), each with propensity to traffic to different tissues and to secrete different cytokines upon activation, have been defined. These fate assignments can be conferred upon iNKT cells during development in the thymus, but the cues that direct these decisions remain unclear. Here, we show that T cell antigen receptor (TCR) signal strength governs the development of iNKT cell subsets in the thymus, with high signaling strength necessary for iNKT2 and iNKT17 development. Alteration of TCR diversity and/or signaling dramatically diminished iNKT2 and iNKT17 cell subset development in a cell intrinsic manner. Decreased TCR signaling affected the persistence of Egr2 expression and the upregulation of PLZF both in vivo and in vitro. Genome-wide chromatin accessibility analysis revealed subset-specific activity of regulatory elements associated with unique signatures of transcription factor binding sites. NFAT and Egr binding motifs were found preferentially enriched in chromatin regulatory regions specifically accessible in iNKT2 cells that were lost in iNKT2 cells that had developed with reduced TCR signaling. Altogether, these data suggest a model of iNKT cell subset development where variable TCR signaling induces changes in chromatin accessibility at NFAT and Egr binding sites which exerts a determinative influence on the dynamic of gene enhancer accessibility that affects the developmental fate of iNKT cells.
2018-05-17 | GSE110327 | GEO