Listeria monocytogenes induces T cell receptor unresponsiveness via its pore-forming toxin listeriolysin O
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE19337 | GEO | 2010/06/29
SECONDARY ACCESSION(S): PRJNA121707
REPOSITORIES: GEO
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Project description:The success of many pathogens relies on their ability to circumvent the innate and adaptive immune defenses. How bacterial pathogens subvert host responses is not clear. Cholesterol-dependent cytolysins (CDCs) represent an expansive family of homologous pore-forming toxins produced by more than 20 Gram-positive bacterial species. Here we show that listeriolysin O (LLO), a prototype CDC produced by Listeria monocytogenes, inhibits antigen receptor-induced T cell proliferation. In vivo proliferation of OT II T cells was highly diminished in the presence of wild type but not the LLO-deficient bacteria. T cells pre-exposed to LLO ex vivo were also impaired in proliferation upon TCR activation in vivo and in vitro. Our results suggest that LLO-induced T cell unresponsiveness is due to the sub-threshold activation of T cells via the induction of a calcium-NFAT dependent transcriptional program that drives the expression of negative regulators of TCR signaling. Keywords: Listerilysin O, Ionomycin, 3 hours stimulation Pooled primary CD4+ T cells isolated from spleen and mesenteric lymph nodes were incubated in either control (Ctrl) medium or medium containing 0.25 ug/ml listeriolysin O (LLO) or 1 uM Ionomycin (Iono) for 3 hours. Thereafter, cells were washed and RNA was prepared.
2010-07-29 | E-GEOD-19337 | biostudies-arrayexpress
Project description:Almost all intracellular bacteria invade host cells through endocytic membrane trafficking. Bacteria that invade through endocytosis are rapidly transported to degradative organelles, therefore bacterial pathogens have evolved strategies to modulate intracellular bactericidal pathways during infection for survival and proliferation. On the other hand, the host cell also has a defensive system (xenophagy, a type of selective autophagy) against pathogens escaping from endosomes.
2022-12-21 | PXD038868 | JPOST Repository
Project description:Almost all intracellular bacteria invade host cells through endocytic membrane trafficking. Bacteria that invade through endocytosis are rapidly transported to degradative organelles, therefore bacterial pathogens have evolved strategies to modulate intracellular bactericidal pathways during infection for survival and proliferation. On the other hand, the host cell also has a defensive system (xenophagy, a type of selective autophagy) against pathogens escaping from endosomes.
2023-05-23 | PXD042419 | JPOST Repository
Project description:Pattern recognition of bacterial products by host receptors is essential for pathogen sensing in many metazoans. Caenorhabditis elegans, however, do not utilize canonical pattern recognition receptors to activate innate immunity toward bacterial pathogens. Whether other mechanisms evolved in nematodes to directly sense pathogens is not known. Here, we characterize the first bacterial pattern recognition receptor and its natural ligand in C. elegans. We show that the C. elegans nuclear hormone receptor NHR-86/HNF4 senses phenazine-1-carboxamide (PCN), a metabolite produced by pathogenic strains of Pseudomonas aeruginosa, to activate protective anti-pathogen defenses in the intestine. PCN binds to the ligand binding domain of NHR-86/HNF4, a ligand-gated transcription factor, which engages a transcriptional program in intestinal epithelial cells that promotes metabolism of toxic phenazines to provide protection against P. aeruginosa. These data de-orphan a nuclear hormone receptor and demonstrate that sensing a metabolite signal of bacterial virulence allows nematodes to detect pathogens in its environment that are poised to cause disease.
2023-02-07 | GSE202258 | GEO
Project description:Exhaustion markers are expressed by T lymphocytes in Follicular Lymphoma (FL). Through these, TIM-3 has been recently identified as a poor pronostic factor when expressed by FL CD4+ T cells. Before this study, there was no molecular characterization of unstimulated CD8+ T cells, expressing - or not - TIM-3. We used microarrays to compare the global gene expression profile between CD8+TIM-3+ T cells and CD8+TIM-3- T cells freshly sorted from follicular lymphoma biopsies. Abstract from the associated publication: Up-regulation of T-cell immunoglobulin-3 (TIM-3) has been associated with negative regulation of the immune response in chronic infection and cancer, including lymphoma. Here, we investigated the possible correlation between TIM-3 expression by ex vivo cytotoxic T cells (CTL) from follicular lymphoma (FL) biopsies and their functional unresponsiveness that could limit the favorable impact of CTL on disease progression. We report a high percentage of CD8+TIM-3+ T cells in lymph nodes of FL patients. When compared to their CD8+TIM-3- counterparts, CD8+TIM-3+ T cells exhibited defective cytokine production following TCR engagement. Furthermore CD8+TIM-3+ T cells display ex vivo markers of lytic granule release and remain unresponsive to further TCR-induced activation of the lytic machinery. Although confocal microscopy showed that TIM-3 expression on CD8+ T cells correlated with minor alterations of immunological synapse, a selective reduction of ERK signaling in CD8+TIM-3+ T cells was observed by phospho-flow analysis. Finally, short relapse free survival despite rituximab(R)-chemotherapy was observed in patients with high content of TIM-3+ cells and a poor infiltrate of granzyme B+ T cells in FL lymph nodes. Together, our data indicate that, besides selective TCR early signaling defects, TIM-3 expression correlates with unresponsiveness of ex vivo CD8+ T cells in FL. They show that scores based on the combination of exhaustion and cytolytic markers in FL microenvironment might be instrumental to identify patients at early risk of relapses following R-chemotherapy.
2016-12-15 | GSE84072 | GEO
Project description:A properly functioning immune system is vital for an organism's wellbeing. Immune tolerance is a critical feature of the immune system that allows immune cells to mount effective responses against exogenous pathogens such as viruses and bacteria, while preventing attack to self-tissues. Activation-induced cell death (AICD) in T lymphocytes, in which repeated stimulations of the T-cell receptor (TCR) lead to activation and then apoptosis of T cells, is a major mechanism for T cell homeostasis and helps maintain peripheral immune tolerance. Defects in AICD can lead to development of autoimmune diseases. Despite its importance, the regulatory mechanisms that underlie AICD remain poorly understood, particularly at an integrative network level. Here, we develop a dynamic multi-pathway model of the integrated TCR signalling network and perform model-based analysis to characterize the network-level properties of AICD. Model simulation and analysis show that amplified activation of the transcriptional factor NFAT in response to repeated TCR stimulations, a phenomenon central to AICD, is tightly modulated by a coupled positive-negative feedback mechanism. NFAT amplification is predominantly enabled by a positive feedback self-regulated by NFAT, while opposed by a NFAT-induced negative feedback via Carabin. Furthermore, model analysis predicts an optimal therapeutic window for drugs that help minimize proliferation while maximize AICD of T cells. Overall, our study provides a comprehensive mathematical model of TCR signalling and model-based analysis offers new network-level insights into the regulation of activation-induced cell death in T cells
Model is encoded by Johannes and submitted to BioModels by Ahmad Zyoud.
2020-03-20 | MODEL2003200003 | BioModels
Project description:A properly functioning immune system is vital for an organism's wellbeing. Immune tolerance is a critical feature of the immune system that allows immune cells to mount effective responses against exogenous pathogens such as viruses and bacteria, while preventing attack to self-tissues. Activation-induced cell death (AICD) in T lymphocytes, in which repeated stimulations of the T-cell receptor (TCR) lead to activation and then apoptosis of T cells, is a major mechanism for T cell homeostasis and helps maintain peripheral immune tolerance. Defects in AICD can lead to development of autoimmune diseases. Despite its importance, the regulatory mechanisms that underlie AICD remain poorly understood, particularly at an integrative network level. Here, we develop a dynamic multi-pathway model of the integrated TCR signalling network and perform model-based analysis to characterize the network-level properties of AICD. Model simulation and analysis show that amplified activation of the transcriptional factor NFAT in response to repeated TCR stimulations, a phenomenon central to AICD, is tightly modulated by a coupled positive-negative feedback mechanism. NFAT amplification is predominantly enabled by a positive feedback self-regulated by NFAT, while opposed by a NFAT-induced negative feedback via Carabin. Furthermore, model analysis predicts an optimal therapeutic window for drugs that help minimize proliferation while maximize AICD of T cells. Overall, our study provides a comprehensive mathematical model of TCR signalling and model-based analysis offers new network-level insights into the regulation of activation-induced cell death in T cells
Model is encoded by Johannes and submitted to BioModels by Ahmad Zyoud.
2020-03-20 | MODEL2003200002 | BioModels
Project description:Interactions between Macrophages and T-lymphocytes: Tumor
Sneaking Through Intrinsic to Helper T cell Dynamics
ROB J. DE BOER AND PAULINE HOGEWEG
Bioinformatics Group, University of Utrecht, Padualaan 8, 3584 CH Utrecht,
The Netherlands
Abstract
In a mathematical model of the cellular immune response we investigate immune
reactions to tumors that are introduced in various doses. The model represents
macrophage T-lymphocyte interactions that generate cytotoxic macrophages and
cytotoxic T-lymphocytes. In this model antigens (tumors) can induce infinitely large
T-lymphocyte effector populations because (a) effector T-lymphocytes are capable
of repeated proliferation and (b) we have omitted immunosuppression. In this
(proliferative) model small doses of weakly antigenic tumors grow infinitely large
(i.e. sneak through) eliciting an immune response of limited magnitude. Intermediate
doses of the same tumor induce larger immune responses and are hence rejected.
Large doses of the tumor break through, but their progressive growth is accompanied
by a strong immune response involving extensive lymphocyte proliferation. Similarly
a more antigenic tumor is rejected in intermediate doses and breaks through in large
doses. Initially small doses however lead to tumor dormancy. Thus although the
model is devoid of explicit regulatory mechanisms that limit the magnitude of its
response (immunosuppression is such a mechanism), the immune response to large
increasing tumors may either be (a) a stable reaction of limited magnitude (experimentally known as tolerance or unresponsiveness) or (b) a strong and ever increasing
reaction. Unresponsiveness can evolve because in this model net T-lymphocyte
proliferation requires the presence of a minimum number of helper T cells (i.e. a
proliferation threshold). Unresponsiveness is caused by depletion of helper T cell
precursors.
2019-12-11 | MODEL1912110001 | BioModels
Project description:While microRNAs (miRs) have been extensively studied in the context of malignancy and tumor progression, their functions in regulating T cell activation are less clear. We found reduced levels of miR-15a/16 at 3-18 h post-T cell receptor (TCR) stimulation, suggesting a role in shaping T cell activation. An inducible miR15a/16 transgenic mouse model was developed to determine how elevating miR-15a/16 levels during early stages of activation would affect T cell proliferation and to identify TCR signaling pathways regulated by this miR pair. Doxycyclin (DOX) induced expression of miR-15a/16 from 0-18 h post-TCR stimulation decreased ex vivo proliferation as well as in vivo antigen-specific proliferation. Bioinformatic and proteomic approaches were combined to identify MEK1 as a target of miR-15a/16. MEK1 targeting by miR-15a/16 was confirmed using miR mimics that decreased MEK1 containing the 3’-UTR target nucleotide sequence (UGCUGCUA) but did not decrease MEK1 containing a mutated control sequence (AAAAAAAA). Phosphorylation of downstream signaling molecules ERK1/2 and Elk1 were decreased with DOX-induced miR-15a/16 expression. In addition to MEK1, ERK1 was subsequently found to be targeted by miR-15a/16, with DOX induced miR-15a/16 reducing total ERK1 levels in T cells. These findings show that TCR stimulation reduces miR-15a/16 levels at early stages of T cell activation to facilitate increased MEK1 and ERK1, and this promotes sustained MEK1-ERK1/2-Elk1 signaling required for optimal proliferation.
2022-04-04 | PXD030935 | Pride
Project description:Bacterial pathogen Burkholderia glumae and fungal pathogen Fusarium graminearum cause similar disease symptoms and often co-isolated from rice heads, inferring interactions between the two pathogens. F. graminearum is resistant to the bacterial toxin toxoflavin, a strong anti-microbial activity, produced by B. glumae. We isolated toxoflavin-sensitive mutants from transcription factor deletion mutant library of F. graminearum. To understand genome-wide transcriptional profiling, we performed RNA-seq analyses of F. graminearum wild-type strain GZ03639 and toxoflavin-sensitive mutant strains (∆GzZC190, ∆GzC2H008, ∆GzbZIP005) under toxoflavin condition.
2018-02-16 | GSE104623 | GEO