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Unregulated APC activation by T cells breaks self-tolerance

ABSTRACT: Unregulated APC activation by T cells breaks self-tolerance

PROVIDER: PRJNA498714 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8115050_1.fastq.gz	Fastqsanger.gz
	SRR8115050_2.fastq.gz	Fastqsanger.gz
	SRR8115045_1.fastq.gz	Fastqsanger.gz
	SRR8115045_2.fastq.gz	Fastqsanger.gz
	SRR8115046_1.fastq.gz	Fastqsanger.gz

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Unregulated APC activation by T cells breaks self-tolerance

Project description:The absence of nTregs results in slight increase of B7 on dendritic cells (DC). Such slightly elevated B7 induce proliferation of T cells with intrinic high self-affinity: bidirectional T/DC interaction ensues, leading to progressive DC activation and reciprocal strong T cell activation.

2019-01-23 | GSE121882 | GEO

Msi1 integrates APC loss and mTORC1 activation to promote intestinal stem cell transformation

Project description:Loss of the APC tumor suppressor in the intestinal epithelium initiates the majority of human colorectal adenocarcinomas. Constitutive Î²-catenin activation is thought to underlie tumorigenesis induced by loss of APC, however Î²-catenin activation alone does not recapitulate all APC-loss phenotypes, suggesting that additional pathways are required. We demonstrate that aberrant activation of the Msi1 RNA binding protein occurs upon APC loss and that constitutive Msi1 activation alone is sufficient to phenocopy APC loss in the intestinal epithelium. Msi1 elicits these effects through binding of mRNAs encoding pleiotropic tumor suppressors resulting in promiscuous activation of quiescent intestinal stem cells, proliferative expansion of the stem cell compartment, crypt fission, and blocked differentiation. Further, we find these phenotypes to be largely dependent on mTORC1 activity, and demonstrate that loss of Msi activity is sufficient to abrogate tumorigenesis in mouse and human systems. Our findings implicate Msi1 as a central coordinator of APC loss-induced intestinal stem cell transformation and adenocarcinoma progression. 2 wild-type, 2 transgenic samples

2015-10-22 | E-GEOD-54598 | biostudies-arrayexpress

Unregulated antigen-presenting cell activation by T cells breaks self tolerance.

Project description:T cells proliferate vigorously following acute depletion of CD4+ Foxp3+ T regulatory cells [natural Tregs (nTregs)] and also when naive T cells are transferred to syngeneic, nTreg-deficient Rag1 -/- hosts. Here, using mice raised in an antigen-free (AF) environment, we show that proliferation in these two situations is directed to self ligands rather than food or commensal antigens. In both situations, the absence of nTregs elevates B7 expression on host dendritic cells (DCs) and enables a small subset of naive CD4 T cells with high self affinity to respond overtly to host DCs: bidirectional T/DC interaction ensues, leading to progressive DC activation and reciprocal strong proliferation of T cells accompanied by peripheral Treg (pTreg) formation. Likewise, high-affinity CD4 T cells proliferate vigorously and form pTregs when cultured with autologous DCs in vitro in the absence of nTregs: this anti-self response is MHCII/peptide dependent and elicited by the raised level of B7 on cultured DCs. The data support a model in which self tolerance is imposed via modulation of CD28 signaling and explains the pathological effects of superagonistic CD28 antibodies.

| S-EPMC6338877 | biostudies-literature

Transcription profiling of intestinal changes in APC deficient intestines following oncogenic Kras activation

Project description:Loss of APC with or without KRAS activation under the control of VilCreER

2020-10-23 | GSE152388 | GEO

Itaconate confers tolerance to late NLRP3 inflammasome activation

Project description:Itaconate confers tolerance to late NLRP3 inflammasome activation

| PRJNA690253 | ENA

Non-deletional CD8+ T cell self-tolerance permits responsiveness but limits tissue damage

Project description:Self-specific CD8+ T cells often escape clonal deletion, but the properties and capabilities of such cells in a physiological setting are unclear. We characterized polyclonal CD8+ T cells specific for the melanocyte antigen tyrosinase-related protein 2 (Trp2) in mice that express or lack this enzyme due to deficiency in Dct, which encodes Trp2. The size, phenotype, and gene expression profile of the pre-immune Trp2/Kb-specific pool were similar in wild-type (WT) and Dct-deficient (Dct-/-) mice. Despite comparable initial responses to Trp2 immunization, WT Trp2/Kb-specific cells showed blunted expansion, and scRNAseq revealed WT cells less readily differentiated into a CD25+ proliferative population. Functional self-tolerance clearly emerged when assessing immunopathology: adoptively transferred WT Trp2/Kb-specific cells mediated vitiligo much less efficiently. Hence, CD8+ T cell self-specificity is poorly predicted by precursor frequency, phenotype or even initial responsiveness, while deficient activation-induced CD25 expression and other gene expression characteristics may help to identify functionally tolerant cells.

2021-04-30 | GSE171221 | GEO

Transcriptional profiling of intestinal changes in Apc Kras tumours with MYC activation and/or drug combination treatment

Project description:Transcriptional profiling of intestinal changes in Apc Kras tumours with MYC activation and/or drug combination treatment

2021-01-01 | GSE159432 | GEO

Breaching self-tolerance to Alu duplex RNA underlies MDA5-mediated inflammation [ADAR1KO HEK293T and WT MDA5]

Project description:Aberrant activation of innate immune receptors can cause a spectrum of immune disorders, such as Aicardi-Goutières syndrome (AGS). One such receptor is MDA5, a viral double-stranded RNA (dsRNA) sensor that induces antiviral immune response. We here demonstrate that constitutive activation of MDA5 in AGS results from the loss of tolerance to cellular dsRNAs formed by Alu retroelements. While wild-type MDA5 cannot efficiently recognize Alu-dsRNA because its filament formation on dsRNA is impaired by the imperfect duplex structure, AGS-variants of MDA5 display reduced sensitivity to duplex structural irregularities, assembling signaling-competent filaments on Alu-dsRNA. Moreover, we identified an unexpected role of RNA-rich cellular environment in suppressing aberrant MDA5 oligomerization, highlighting context-dependence of self vs. non-self discrimination. Overall, our work demonstrates that the increased efficiency of MDA5 to recognize dsRNA comes at a cost of self-recognition, and implicates a unique role of Alu RNAs as virus-like elements that shape the primate immune system.

2018-01-29 | GSE104864 | GEO

Breaching self-tolerance to Alu duplex RNA underlies MDA5-mediated inflammation [WT HEK293T and mutant MDA5]

2018-01-29 | GSE103539 | GEO

Transcription profiling of mouse liver in conditional knockouts of the tumor suppressor gene Apc identifies Wnt/bet-catenin signaling activation in hepatocytes

Project description:A "Cartes d'Identite des Tumeurs" (CIT) project from the french Ligue Nationale Contre le Cancer (http://cit.ligue-cancer.net). Conditional Knockout mouse model for the tumor suppressor gene Ap, Apc 2lox. The disruption of the Apc gene is realized by injection of an adenovirus encoding the Cre recombinase (AdCre). Homozygous animals injected with a high dose of AdCre showed an activation of the Wnt/beta-catenin signaling in most of the hepatocytes and develop an hepatomegaly and die soon after. Analysis of gene up- and down regulation for liver-indicible APC disruption.

2006-03-13 | E-TABM-81 | biostudies-arrayexpress

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