Foxp3 expression diversifies the metabolic capacity and enhances the efficacy of CD8 T cells in adoptive T cell therapy
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA853261 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19860305_1.fastq.gz | Fastqsanger.gz | |||
| SRR19860305_2.fastq.gz | Fastqsanger.gz | |||
| SRR19860306_1.fastq.gz | Fastqsanger.gz | |||
| SRR19860306_2.fastq.gz | Fastqsanger.gz | |||
| SRR19860307_1.fastq.gz | Fastqsanger.gz |
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Project description:CD4 regulatory T cells overwhelm conventional T cells in the tumor microenvironment (TME) thanks to a Foxp3-driven metabolic program that allows them to use alternate substrate and engage different metabolic pathways. In this study, we proposed to overexpress Foxp3 in CD8 T cells (CTL) and examine how it affected their antitumor properties. We show that Foxp3 overexpressing (Foxp3UP) CTLs proliferated and markedly accumulated in the TME while showing enhanced cytotoxicity and antitumor efficacy but not suppressor activity. Interestingly, tumor-infiltrating Foxp3UP CTLs exhibited a T-cell effector and leukocyte migration genetic signature, and positive enrichment in glycolysis, fatty acid (FA) metabolism and oxidative phosphorylation (OXPHOS) pathways. Intratumoral Foxp3UP CTLs showed an increased expression of Glut1, enhanced glucose and FA uptake and intracellular lipid accumulation. Interestingly, Foxp3UP CTLs compensated for the loss of mitochondrial respiration-driven ATP production by activating aerobic glycolysis. Moreover, in limiting nutrient conditions these cells engaged FA oxidation to drive OXPHOS for their energetic demands. Further, their ability to couple glycolysis and OXPHOS allowed then to sustain proliferation under glucose restriction. Our findings demonstrate a hitherto unknown role of Foxp3 in the adaptation of CTLs to TME that can be used to enhance their efficacy in adoptive T cell therapy
2022-10-15 | GSE206987 | GEO
Project description:Regulatory T cells overwhelm conventional T cells in the tumor microenvironment (TME) thanks to a FOXP3-driven metabolic program that allows them to engage different metabolic pathways. Using a melanoma model of adoptive T cell therapy (ACT), we show that FOXP3 overexpression in mature CD8 T cells improved their antitumor efficacy, favoring their tumor recruitment, proliferation, and cytotoxicity. FOXP3-overexpressing (Foxp3UP) CD8 T cells exhibited features of tissue-resident memory-like and effector T cells, but not suppressor activity. Transcriptomic analysis of tumor-infiltrating Foxp3UP CD8 T cells showed positive enrichment in a wide variety of metabolic pathways, such as glycolysis, fatty acid (FA) metabolism, and oxidative phosphorylation (OXPHOS). Intratumoral Foxp3UP CD8 T cells exhibited an enhanced capacity for glucose and FA uptake as well as accumulation of intracellular lipids. Interestingly, Foxp3UP CD8 T cells compensated for the loss of mitochondrial respiration-driven ATP production by activating aerobic glycolysis. Moreover, in limiting nutrient conditions these cells engaged FA oxidation to drive OXPHOS for their energy demands. Importantly, their ability to couple glycolysis and OXPHOS allowed them to sustain proliferation under glucose restriction. Our findings demonstrate a hitherto unknown role for FOXP3 in the adaptation of CD8 T cells to TME that may enhance their efficacy in ACT.
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Project description:Regulatory T cells have been shown to adopt a catabolic metabolic programme with increased capacity for fatty acid oxidation fuelled oxidative phosphorylation (OXPHOS). The role of Foxp3 in this metabolic shift is poorly understood. Here we show that Foxp3 was sufficient to induce a significant increase in the spare respiratory capacity of the cell, the extra OXPHOS capacity available to a cell to increased demands on energy in response to work. Foxp3-expressing cells were enhanced in their ability to utilise palmitate for respiration and in addition the activity of electron transport complexes I, II and IV were enhanced following Foxp3 expression. ATP was secreted by both T effector and regulatory T cells and was reduced by mitochondrial respiration inhibitors. Thus Foxp3 imparts a selective advantage in ATP generation capacity to the cell and may exploit this as a source of adenosine for functional immunomodulation. In order to explore possible mechanisms for these differences in metabolism we conducted a comparative quantitative proteomics study to compare the contribution of TGFβ and the transcription factor Foxp3 to the Treg proteome. We used quantitative mass spectrometry to examine differences between proteomes of nuclear and cytoplasmic Foxp3-containing T cells and Foxp3 positive iTreg and Foxp3 negative activated CD4 T cells in addition to human peripheral blood natural Treg. Gene set enrichment analysis of our proteomic datasets demonstrated that Foxp3 drives a significant up regulation of several members of the mitochondrial electron transport chain.
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Project description:Treg cells bearing a diverse antigen receptor repertoire suppress pathogenic T cells and maintain immune homeostasis during their long lifespan. How their robust function is determined genetically remains elusive. Here, we investigate the regulatory space of the cis-regulatory elements of Treg lineage–specifying factor Foxp3. Foxp3 enhancers are known as distinct readers for environmental cues in promoting Treg cell induction or lineage stability. However, their single deficiencies cause mild, if any, immune dysregulation, leaving the key transcriptional mechanisms determining Foxp3 expression and thereby Treg suppressive capacity uncertain. We examined the collective activities of Foxp3 enhancers and found that they coordinate to maximize Treg cell induction, Foxp3 expression level, or lineage stability through distinct modes and that ablation of synergistic enhancers led to lethal autoimmunity in young mice. Thus, the induction and maintenance of a diverse, stable Treg cell repertoire rely on combinatorial Foxp3 enhancers, suggesting broad, stage-specific, synergistic activities of cell-intrinsic factors and -extrinsic cues in determining Treg suppressive capacity.
2021-05-10 | GSE169385 | GEO
Project description:Treg cells bearing a diverse antigen receptor repertoire suppress pathogenic T cells and maintain immune homeostasis during their long lifespan. How their robust function is determined genetically remains elusive. Here, we investigate the regulatory space of the cis-regulatory elements of Treg lineage–specifying factor Foxp3. Foxp3 enhancers are known as distinct readers for environmental cues in promoting Treg cell induction or lineage stability. However, their single deficiencies cause mild, if any, immune dysregulation, leaving the key transcriptional mechanisms determining Foxp3 expression and thereby Treg suppressive capacity uncertain. We examined the collective activities of Foxp3 enhancers and found that they coordinate to maximize Treg cell induction, Foxp3 expression level, or lineage stability through distinct modes and that ablation of synergistic enhancers led to lethal autoimmunity in young mice. Thus, the induction and maintenance of a diverse, stable Treg cell repertoire rely on combinatorial Foxp3 enhancers, suggesting broad, stage-specific, synergistic activities of cell-intrinsic factors and -extrinsic cues in determining Treg suppressive capacity.
2021-05-10 | GSE169228 | GEO
Project description:Treg cells bearing a diverse antigen receptor repertoire suppress pathogenic T cells and maintain immune homeostasis during their long lifespan. How their robust function is determined genetically remains elusive. Here, we investigate the regulatory space of the cis-regulatory elements of Treg lineage–specifying factor Foxp3. Foxp3 enhancers are known as distinct readers for environmental cues in promoting Treg cell induction or lineage stability. However, their single deficiencies cause mild, if any, immune dysregulation, leaving the key transcriptional mechanisms determining Foxp3 expression and thereby Treg suppressive capacity uncertain. We examined the collective activities of Foxp3 enhancers and found that they coordinate to maximize Treg cell induction, Foxp3 expression level, or lineage stability through distinct modes and that ablation of synergistic enhancers led to lethal autoimmunity in young mice. Thus, the induction and maintenance of a diverse, stable Treg cell repertoire rely on combinatorial Foxp3 enhancers, suggesting broad, stage-specific, synergistic activities of cell-intrinsic factors and -extrinsic cues in determining Treg suppressive capacity.
2021-05-10 | GSE158107 | GEO
Project description:Treg cells bearing a diverse antigen receptor repertoire suppress pathogenic T cells and maintain immune homeostasis during their long lifespan. How their robust function is determined genetically remains elusive. Here, we investigate the regulatory space of the cis-regulatory elements of Treg lineage–specifying factor Foxp3. Foxp3 enhancers are known as distinct readers for environmental cues in promoting Treg cell induction or lineage stability. However, their single deficiencies cause mild, if any, immune dysregulation, leaving the key transcriptional mechanisms determining Foxp3 expression and thereby Treg suppressive capacity uncertain. We examined the collective activities of Foxp3 enhancers and found that they coordinate to maximize Treg cell induction, Foxp3 expression level, or lineage stability through distinct modes and that ablation of synergistic enhancers led to lethal autoimmunity in young mice. Thus, the induction and maintenance of a diverse, stable Treg cell repertoire rely on combinatorial Foxp3 enhancers, suggesting broad, stage-specific, synergistic activities of cell-intrinsic factors and -extrinsic cues in determining Treg suppressive capacity.
2021-05-10 | GSE158105 | GEO
Project description:Treg cells bearing a diverse antigen receptor repertoire suppress pathogenic T cells and maintain immune homeostasis during their long lifespan. How their robust function is determined genetically remains elusive. Here, we investigate the regulatory space of the cis-regulatory elements of Treg lineage–specifying factor Foxp3. Foxp3 enhancers are known as distinct readers for environmental cues in promoting Treg cell induction or lineage stability. However, their single deficiencies cause mild, if any, immune dysregulation, leaving the key transcriptional mechanisms determining Foxp3 expression and thereby Treg suppressive capacity uncertain. We examined the collective activities of Foxp3 enhancers and found that they coordinate to maximize Treg cell induction, Foxp3 expression level, or lineage stability through distinct modes and that ablation of synergistic enhancers led to lethal autoimmunity in young mice. Thus, the induction and maintenance of a diverse, stable Treg cell repertoire rely on combinatorial Foxp3 enhancers, suggesting broad, stage-specific, synergistic activities of cell-intrinsic factors and -extrinsic cues in determining Treg suppressive capacity.
2021-05-10 | GSE158222 | GEO
Project description:Foxp3 enhancers synergize to maximize regulatory T cell suppressive capacity
| PRJNA664381 | ENA
Project description:Regulatory T cells (Treg) have been shown to adopt a catabolic metabolic programme with increased capacity for fatty acid oxidation fuelled oxidative phosphorylation (OXPHOS). The role of Foxp3 in this metabolic shift is poorly understood. Here we show that Foxp3 was sufficient to induce a significant increase in the spare respiratory capacity of the cell, the extra OXPHOS capacity available to a cell to meet increased demands on energy in response to work. Foxp3-expressing cells were enhanced in their ability to utilise palmitate for respiration and, in addition, the activity of electron transport complexes I, II and IV were enhanced following Foxp3 expression. Foxp3 also imparts a selective advantage in ATP generation capacity, one that might be exploited as a source of adenosine for functional immunomodulation. In order to explore possible mechanisms for these differences in metabolism we conducted a quantitative proteomics study to compare the contribution of TGFβ and the transcription factor Foxp3 to the Treg proteome. We used quantitative mass spectrometry to examine differences between proteomes of nuclear and cytoplasmic Foxp3-containing CD4+ T cells from various sources with Foxp3- activated CD4 T cells, as well as Treg from human peripheral blood. Gene set enrichment analysis of our proteomic datasets demonstrated that Foxp3 expression is associated with a significant up regulation of several members of the mitochondrial electron transport chain. Not only does Foxp3 influence genes directly concerned with immune function, but also with the energy generating functions of Treg.
2017-02-15 | PXD001906 | Pride