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A genetic circuitry linking Id-proteins (Id2 and Id3) and the AKT-FOXO-mTORC1 axis to suppress innate-variant TFH cell development, maintain T cell quiescence and prevent lymphomagenesis.

ABSTRACT: It is now well established that the E- and Id-protein axis regulates multiple steps in lymphocyte development. However, it remains unknown as to how E- and Id-proteins mechanistically enforce and maintain the naïve T cell fate. Here we show that Id2 and Id3 suppressed the development and expansion of innate-variant TFH cells. Innate-variant TFH cells required MHC Class I-like signalling and were associated with germinal center B cell development. We found that Id2 and Id3 induced Foxo1 and Foxp1 expression to antagonize the activation of TFH transcription signature. We show that Id2 and Id3 acted upstream of the Hif1a/Foxo/AKT/mTORC1 pathway as well as the c-myc/p19Arf module to control cellular expansion and activation. We found that mice depleted for Id2 and Id3 expression developed colitis and αβ T cell lymphomas. Lymphomas depleted for Id2 and Id3 expression displayed elevated levels of c-myc whereas p19Arf abundance declined. Transcription signatures of Id2- and Id3-depleted lymphomas revealed similarities with genetic deficiencies associated with Burkitt lymphoma. We propose that in response to antigen receptor and/or cytokine signaling the E-Id protein axis modulates the activities of the PI3K-AKT-mTORC1-Hifa and c-myc/p19Arf pathways to control cellular expansion and homeostatic proliferation.

ORGANISM(S): Mus musculus

PROVIDER: GSE64779 | GEO | 2015/03/04

SECONDARY ACCESSION(S): PRJNA271860

REPOSITORIES: GEO

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A genetic circuitry linking Id-proteins (Id2 and Id3) and the AKT-FOXO-mTORC1 axis to suppress innate-variant TFH cell development, maintain T cell quiescence and prevent lymphomagenesis.

Project description:It is now well established that the E- and Id-protein axis regulates multiple steps in lymphocyte development. However, it remains unknown as to how E- and Id-proteins mechanistically enforce and maintain the naïve T cell fate. Here we show that Id2 and Id3 suppressed the development and expansion of innate-variant TFH cells. Innate-variant TFH cells required MHC Class I-like signalling and were associated with germinal center B cell development. We found that Id2 and Id3 induced Foxo1 and Foxp1 expression to antagonize the activation of TFH transcription signature. We show that Id2 and Id3 acted upstream of the Hif1a/Foxo/AKT/mTORC1 pathway as well as the c-myc/p19Arf module to control cellular expansion and activation. We found that mice depleted for Id2 and Id3 expression developed colitis and αβ T cell lymphomas. Lymphomas depleted for Id2 and Id3 expression displayed elevated levels of c-myc whereas p19Arf abundance declined. Transcription signatures of Id2- and Id3-depleted lymphomas revealed similarities with genetic deficiencies associated with Burkitt lymphoma. We propose that in response to antigen receptor and/or cytokine signaling the E-Id protein axis modulates the activities of the PI3K-AKT-mTORC1-Hifa and c-myc/p19Arf pathways to control cellular expansion and homeostatic proliferation. RNA-seq data of 5 of wild type CD4SP cells, 3 of wild type Tfh cells, 3 of Id3-/- CD4SP cells, 3 of Id2-/-Id3-/-(dKO) CD4SP cells, and 6 of Id2-/-Id3-/- lymphoma cells.

2015-03-04 | E-GEOD-64779 | biostudies-arrayexpress

Gene expression in neonatal NKT cells and lymphoma samples from mice with high E protein levels [Microarray Expression]

Project description:Inhibitor of DNA binding proteins (ID), including Id1-4, are transcriptional regulators involved in promoting cell proliferation and survival in various cell types. Although upregulation of Id proteins have been widely reported to be associated with a broad spectrum of tumors, recent studies have identified that Id3 also plays a tumor suppressor role in the development of Burkitt’s lymphoma in humans and Hepatosplenic T cell lymphomas in mice. However, there is a lack of evidence to suggest the tumor suppressor roles for other Id genes, particularly Id2, which is highly expressed in many T lymphocytes. In this study we report that Id2 plays a tumor suppressive role in collaboration with Id3 in developing T cells in mice. We found that there was rapid lymphoma development in Id2f/fId3f/fLckCre mice caused by unchecked neonatal expansion of invariant Natural Killer T (iNKT) cells and a unique subset of innate-like, CD1d-independent T cells. These tumors also gave rise to lymphomas in Rag-deficient mice, reaffirming the inherent tumorigenic potential of these cells. Microarray analysis revealed a significantly modified program in expanding iNKT cells that ultimately contributed to tumorigenesis. We found chromosome instability and significant upregulation of several different signaling pathways, including pathways for multiple chemokines, cytokines and their receptors, in these tumors. While Id proteins are being considered as potential therapeutic targets in some cancer models, our results highlight the possibility of aggravated tumorigenesis upon suppression of Id2 and Id3.

2017-04-20 | GSE73864 | GEO

Gene expression in neonatal NKT cells and lymphoma samples from mice with high E protein levels [Microarray Expression]

Project description:Inhibitor of DNA binding proteins (ID), including Id1-4, are transcriptional regulators involved in promoting cell proliferation and survival in various cell types. Although upregulation of Id proteins have been widely reported to be associated with a broad spectrum of tumors, recent studies have identified that Id3 also plays a tumor suppressor role in the development of Burkittâ??s lymphoma in humans and Hepatosplenic T cell lymphomas in mice. However, there is a lack of evidence to suggest the tumor suppressor roles for other Id genes, particularly Id2, which is highly expressed in many T lymphocytes. In this study we report that Id2 plays a tumor suppressive role in collaboration with Id3 in developing T cells in mice. We found that there was rapid lymphoma development in Id2f/fId3f/fLckCre mice caused by unchecked neonatal expansion of invariant Natural Killer T (iNKT) cells and a unique subset of innate-like, CD1d-independent T cells. These tumors also gave rise to lymphomas in Rag-deficient mice, reaffirming the inherent tumorigenic potential of these cells. Microarray analysis revealed a significantly modified program in expanding iNKT cells that ultimately contributed to tumorigenesis. We found chromosome instability and significant upregulation of several different signaling pathways, including pathways for multiple chemokines, cytokines and their receptors, in these tumors. While Id proteins are being considered as potential therapeutic targets in some cancer models, our results highlight the possibility of aggravated tumorigenesis upon suppression of Id2 and Id3. Pre-malignant iNKT (TCRÎ²+CD1dTet+) cells were sorted from three 20 day old L-DKO mice. Lymphoma cells (T cells that are CD1dTet+ or CD1dTet-) were sorted from tissues of 18-37 week old L-DKO mice. Total RNA was extracted, and mRNA profiling was done using GeneChip Mouse Genome 430A 2.0 arrays (GPL8321, Affymetrix)

2017-04-20 | E-GEOD-73864 | biostudies-arrayexpress

Gene expression in neonatal NKT cells and lymphoma samples from mice with high E protein levels [RNA-Seq]

Project description:Inhibitor of DNA binding proteins (ID), including Id1-4, are transcriptional regulators involved in promoting cell proliferation and survival in various cell types. Although upregulation of Id proteins have been widely reported to be associated with a broad spectrum of tumors, recent studies have identified that Id3 also plays a tumor suppressor role in the development of Burkitt’s lymphoma in humans and Hepatosplenic T cell lymphomas in mice. However, there is a lack of evidence to suggest the tumor suppressor roles for other Id genes, particularly Id2, which is highly expressed in many T lymphocytes. In this study we report that Id2 plays a tumor suppressive role in collaboration with Id3 in developing T cells in mice. We found that there was rapid lymphoma development in Id2f/fId3f/fLckCre mice caused by unchecked neonatal expansion of invariant Natural Killer T (iNKT) cells and a unique subset of innate-like, CD1d-independent T cells. These tumors also gave rise to lymphomas in Rag-deficient mice, reaffirming the inherent tumorigenic potential of these cells. Microarray analysis revealed a significantly modified program in expanding iNKT cells that ultimately contributed to tumorigenesis. Similar pathways in CD1dTet- tumors were verified by RNASeq. We found chromosome instability and significant upregulation of several different signaling pathways, including pathways for multiple chemokines, cytokines and their receptors, in these tumors. While Id proteins are being considered as potential therapeutic targets in some cancer models, our results highlight the possibility of aggravated tumorigenesis upon suppression of Id2 and Id3.

2017-04-20 | GSE83760 | GEO

The Id-RAP1 axis is essential for glioma maintenance and residency of glioma cells in the perivascular niche

Project description:The experiment was designed to achieve Cre recombinase mediated deletion of Id1, Id2 and Id3 in a temporally controlled fashion in tumor cells of Id1, Id2, Id3 floxed mice with the aim of comparing the gene expression profiles of Id expressing versus Id deleted tumors.

2013-04-30 | E-MTAB-1303 | biostudies-arrayexpress

Id proteins suppress E2A-driven iNKT cell development prior to TCR selection [RNA-seq_new]

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

Id proteins suppress E2A-driven iNKT cell development prior to TCR selection [ChIP-seq]

2018-01-23 | GSE89847 | GEO

Id proteins suppress E2A-driven iNKT cell development prior to TCR selection [RNA-seq]

2018-01-23 | GSE89848 | GEO

Id2 is required for antiviral Th1 cell differentiation and represses Tfh cell differentiation

Project description:Differentiation of naive CD4+ T cells into T-helper (Th) effector subsets is critical for protection against pathogens. Together, E-protein transcription factors and the inhibitor-of-DNA binding (Id) proteins are important arbiters of T cell development, but their role in the differentiation of Th1 and Tfh cells is not well understood. Th1 cells show robust Id2 expression compared to Tfh cells, and RNAi depletion of Id2 increased Tfh cell frequencies and germinal center responses, while impairing Th1 cell accumulation during viral infection. Further, Th1 cell differentiation was blocked by genetic ablation of Id2, leading to E-protein dependent accumulation of effector cells with 78% of Th1-associated genes showing diminished expression and a concurrent enrichment of the Tfh gene-expression program. The Tfh-defining transcriptional repressor Bcl6 bound to the Id2 locus inhibiting expression, providing a mechanism by which bimodal expression of Id2 in Tfh and Th1 cells can be established. Thus, Id2 is critical in enforcing the reciprocal development of Th1 and Tfh cell fates. We used microarray to assess the changes in gene expression between Id2-sufficient and -deficient Th1 and Tfh cells.

2016-05-23 | GSE74854 | GEO

Expression data from sorted Id3-GFP hi Id2-YFP int and Id3-GFP lo Id2-YFP hi activated CD8 T cells

Project description:During an immune response, CD8 T cells fall along a gradient of memory potential, but the regulators of these fate decsisions are not well understood. We utlized Id3-GFP and Id2-YFP reporter mice to elucidate the role of Id3 and Id2 during early CD8 T cell differentiation by gene expression. Id3-GFP hi Id2-YFP int or Id3-GFP lo Id2-YFP hi OT-I cells were sorted into trizol at day 6 of VSV-OVA infection and analyzed by microarray

2011-10-06 | E-GEOD-32675 | biostudies-arrayexpress

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