Immunological History Governs Human Stem Cell Memory CD4 Heterogeneity Via The Wnt Signaling Pathway
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA599321 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10840100_1.fastq.gz | Fastqsanger.gz | |||
| SRR10840100_2.fastq.gz | Fastqsanger.gz | |||
| SRR10840200_1.fastq.gz | Fastqsanger.gz | |||
| SRR10840200_2.fastq.gz | Fastqsanger.gz | |||
| SRR10840300_1.fastq.gz | Fastqsanger.gz |
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Project description:The diversity of the naïve T cell repertoire drives the replenishment potential and capacity of memory T cells to respond to immune challenges. Attrition of the immune system is associated with an increased prevalence of pathologies in aged individuals, but whether stem cell memory T lymphocytes (TSCM) contribute to such attrition is still unclear. Using single cells RNA sequencing and high-dimensional flow cytometry, we demonstrate that TSCM heterogeneity results from differential engagement of Wnt signaling. In humans, aging is associated with the coupled loss of Wnt/β-catenin signature in CD4 TSCM and systemic increase in the levels of Dickkopf-related protein 1, a natural inhibitor of the Wnt/β-catenin pathway. Functional assays support recent thymic emigrants as the precursors of CD4 TSCM. Our data thus hint that reversing TSCM defects by metabolic targeting of the Wnt/β-catenin pathway may be a viable approach to restore and preserve immune homeostasis in the context of immunological history.
| S-EPMC7010798 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2020-01-08 | GSE143215 | GEO
Project description:This a model from the article:
Evolution of immunological memory and the regulation of competition between
pathogens.
Wodarz D. Curr Biol
2003 Sep 16;13(18):1648-52 13678598
,
Abstract:
Memory is a central characteristic of immune responses. It is defined as an
elevated number of specific immune cells that remain after resolution of
infection and can protect the host against reinfection. The evolution of
immunological memory is subject to debate. The advantages of memory discussed so
far include protection from reinfection, control of chronic infection, and the
transfer of immune function to the next generation. Mathematical models are used
to identify a new force that can drive the evolution of immunological memory:
the duration of memory can regulate the degree of competition between different
pathogens. While a long duration of memory provides lasting protection against
reinfection, it may also allow an inferior pathogen species to persist. This can
be detrimental for the host if the inferior pathogen is more virulent. On the
other hand, a shorter duration of memory ensures that an inferior pathogen
species is excluded. This can be beneficial for the host if the inferior
pathogen is more virulent. Thus, while in the absence of pathogen diversity
memory is always expected to evolve to a long duration, under specific
circumstances, memory can evolve toward shorter durations in the presence of
pathogen diversity.
This model was taken from the CellML repository
and automatically converted to SBML.
The original model was:
Wodarz D. (2003) - version=1.0
The original CellML model was created by:
Catherine Lloyd
c.lloyd@auckland.ac.nz
The University of Auckland
This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team.
To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication
for more information.
In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not..
To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
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Project description:Highly Immunogenic Cancer Cells Require Activation of the WNT Pathway for Immunological Escape
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Project description:PD-1 blockade therapy exerts antitumor effects by restoring the infiltration of tumor antigen-specific CD8+ T cells. While neoantigens arising from gene alterations in cancer cells comprise critical tumor antigens in antitumor immunity, a subset of non-small-cell lung cancers (NSCLCs) harboring substantial tumor mutation burden (TMB) lack CD8+ T cells in the tumor microenvironment (TME), resulting in resistance to PD-1 blockade therapy. This resistance is an urgent issue, so the mechanism(s) mediating impaired antitumor immunity in highly mutated NSCLCs need to be explored. Here, we show that activation of the WNT/b-catenin signaling pathway contributes to the development of a noninflamed TME in tumors with high TMB. NSCLCs that lack immune cell infiltration into the TME despite high TMB preferentially upregulate the WNT/b-catenin pathway. Immunological assays revealed that those patients harbored neoantigen-specific CD8+ T cells in the peripheral blood but not in the TME, suggesting impaired T cell infiltration into the TME due to the activation of WNT/b-catenin signaling. In our animal model, the accumulation of gene mutations in cancer cells increased CD8+ T cell infiltration into the TME, slowing tumor growth. However, further accumulation of gene mutations blunted antitumor immunity by excluding CD8+ T cells from tumors in a WNT/b-catenin signaling-dependent manner. Combined treatment with PD-1 blockade and WNT/b-catenin signaling inhibitors induced far stronger antitumor immunity than either treatment alone. We propose a mechanism-oriented combination therapy concept in the cancer immunotherapy field, i.e., the combination of immune checkpoint inhibitors with drugs that target specific molecules in cancer cell-intrinsic oncogenic signaling pathways involved in immune escape.
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Project description:Human CD127 negative ILC2s show immunological memory.
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Project description:Immunological memory is generally thought to be mediated exclusively by lymphocytes such as memory T and B cells. However, enhanced innate immune responses caused by a previous infection increase protection against reinfection suggesting the presence of innate immunological memory. Here, we describe expression profile of peritoneal macrophages from wild-type mice pre-administrated with TLR ligands or from ATF7 knockout mice. ATF7 suppresses a group of innate-immunity genes in macrophage by recruiting H3K9 dimethyltransferase G9a. TLR ligands induce ATF7 phosphorylation, leading to release of ATF7 from chromatin and reduction in H3K9me2 level. Partially disrupted chromatin structure and increased basal expression on target genes are maintained for a long period, increasing resistance pathogens. Therefore we speculate ATF7 is important factor in controlling innate immunological memory. This series contains seven sets of exression array data. For all sample, we use four CEL files generated by four biological-independent experiments.
2015-08-31 | E-GEOD-71111 | biostudies-arrayexpress
Project description:Immunological memory is generally thought to be mediated exclusively by lymphocytes such as memory T and B cells. However, enhanced innate immune responses caused by a previous infection increase protection against reinfection suggesting the presence of innate immunological memory. Here, we describe 3,811 ATF7 binding sites in mouse peritoneal macrophages, and 95% of the ATF7 signals in wild-type macrophages are lost in ATF7 knockout macrophages. ATF7 suppresses a group of innate-immunity genes in macrophage by recruiting H3K9 dimethyltransferase G9a. TLR ligands induce ATF7 phosphorylation, leading to release of ATF7 from chromatin and reduction in H3K9me2 level. Partially disrupted chromatin structure and increased basal expression on target genes are maintained for a long period, increasing resistance pathogens. Therefore we speculate ATF7 is important factor in controlling innate immunological memory. This series contains one set of whole genome ChIP-chip data and 2 sets of promoter array ChIP-chip data. For all sample, we use three IP .CEL files and three WCE .CEL files (they are triplicated experiments) to make one profile.
2015-08-31 | E-GEOD-71112 | biostudies-arrayexpress
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Project description:Understanding the mechanisms underlying tumor heterogeneity is key to development of treatments that can target specific tumor subtypes. We have previously targeted CRE recombinase-dependent conditional deletion of the tumor suppressor genes Brca1, Brca2, p53 and/or Pten to basal or luminal ER- cells of the mouse mammary epithelium. We demonstrated that both the cell-of-origin and the tumor-initiating genetic lesions co-operate to influence mammary tumor phenotype. Here, we use a CRE-activated HER2 orthologue to specifically target HER2/ERBB2 oncogenic activity to basal or luminal ER- mammary epithelial cells and carry out a detailed analysis of the tumors which develop. We find that in contrast to our previous studies, basal epithelial cells are refractory to transformation by the activated NeuKI allele, with mammary epithelial tumor formation largely confined to luminal ER- cells. Histologically, the majority of tumors that developed were classified as either adenocarcinomas of no special type or metaplastic adenosquamous tumors. Remarkably, the former were more strongly associated with virgin animals and were typically characterised by amplification of the NeuNT/ErbB2 locus and activation of non-canonical WNT signalling. In contrast, tumors characterised by squamous metaplasia were associated with animals that had been through at least one pregnancy and typically had lower levels of NeuNT/ErbB2 locus amplification but had activated canonical WNT signalling. Squamous changes in these tumors were associated with activation of the Epidermal Differentiation Cluster. Thus, in this model of HER2 breast cancer, cell-of-origin, reproductive history, NeuNT/ErbB2 locus amplification, and the activation of specific branches of the WNT signalling pathway all interact to drive inter-tumor heterogeneity.
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