Mitochondrial integrity regulated by FABP5 is a cell-intrinsic checkpoint for Treg suppressive function
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ABSTRACT:
PROVIDER: PRJNA521378 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8545710_1.fastq.gz | Fastqsanger.gz | |||
| SRR8545710_2.fastq.gz | Fastqsanger.gz | |||
| SRR8545711_1.fastq.gz | Fastqsanger.gz | |||
| SRR8545711_2.fastq.gz | Fastqsanger.gz | |||
| SRR8545704_1.fastq.gz | Fastqsanger.gz |
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Project description:Regulatory T cells (Tregs) negatively regulate immune-mediated inflammation that is essential for preventing autoimmunity, but which can be detrimental in cancer. Central to Treg activation are changes in lipid metabolism to support their survival and function. Fatty acid binding proteins (FABPs) are a family of lipid chaperones required to facilitate the uptake and trafficking of intracellular lipids. One family member, FABP5, is expressed in certain T cell subsets, but its function remains elusive. We show here that in Tregs, FABP5 inhibition causes mitochondrial defects, underscored by decreased OXPHOS, lipid elongation and desaturation, and loss of cristae structure, which augment their suppressive function. Mitochondrial dysfunction after FABP5 inhibition results in mtDNA release and consequent cGAS/STING-dependent type I IFN signaling, which induces increased production of the regulatory cytokine IL-10, promoting Treg cell suppressive activity. Together these data reveal that FABP5 acts as a gatekeeper of mitochondrial health to control Treg cell function.
2019-12-26 | GSE126245 | GEO
Project description:Analysis of the transcriptional correlates of FOXP3 expression in suppressive and non-suppressive primary human Treg cell clones. Individual CD4+CD25High or Cd4+CD25- T cells were isolated from human PBMCs and expanded in vitro. After 3 weeks of expansion, individual clones were analysed for FOXP3 expression and in vitro suppressive activity against freshly sorted allogeneic effector T cells. This study analyses the total RNA isolated from FOXP3+ clones with suppressive potency to their non-suppressive counterparts. The resutls of this study should provide insights into the molecular pathways linking FOXP3 expression to distinct aspects of Treg phenotype and function. Total RNA obtained from individual clones of primary human regulatory and effector CD4+T cells.
2015-05-06 | E-GEOD-65650 | biostudies-arrayexpress
Project description:Analysis of the transcriptional correlates of FOXP3 expression in suppressive and non-suppressive primary human Treg cell clones. Individual CD4+CD25High or Cd4+CD25- T cells were isolated from human PBMCs and expanded in vitro. After 3 weeks of expansion, individual clones were analysed for FOXP3 expression and in vitro suppressive activity against freshly sorted allogeneic effector T cells. This study analyses the total RNA isolated from FOXP3+ clones with suppressive potency to their non-suppressive counterparts. The resutls of this study should provide insights into the molecular pathways linking FOXP3 expression to distinct aspects of Treg phenotype and function.
2015-05-06 | GSE65650 | GEO
Project description:Purpose: Mouse BMDM is the universal cell type of studying innate immunity. This study was designed to analyze LPS induced innate immune response and the gene expression in FABP5 KO BMDMs with overexpression of FABP5 WT or FABP5 C127S. Methods: FABP5 KO BMDMs were nucleofected with 5 μg pXJ40-3xFlag-FABP5 WT or C127S plasmid using the Amaxa Mouse Macrophage Nucleofector Kit (Lonza, VPA-1009) following the manufacturer’s instructions. Replace medium 6 hours post Nucleofection and add 500 ng/mL LPS to the fresh medium. 24 hours after treatment, harvest cells by using GenElute Single Cell RNA Purification Kit (Sigma, RNB300) and perform RNA-seq. Then mRNA profiles of these samples were generated by high-throughput sequencing analysis, using Illumina NovaSeq6000. And the differential mRNA profiles were analyzed. Results: mRNA profiles were analyzed, and differential expression profiles were compared. Conclusions: Our study demonstrated the transcriptional profiles of FABP5 KO BMDMs with overexpression of FABP5 WT or FABP5 C127S upon LPS treatment, with biologic replicates, generated by RNA-seq technology.
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Project description:Regulatory T cells (Tregs) subdue immune responses. Central to Treg activation are changes in lipid metabolism that support their survival and function. Fatty acid binding proteins (FABPs) are a family of lipid chaperones required to facilitate uptake and intracellular lipid trafficking. One family member, FABP5, is expressed in T cells, but its function remains unclear. We show that in Tregs, genetic or pharmacologic inhibition of FABP5 function causes mitochondrial changes underscored by decreased OXPHOS, impaired lipid metabolism, and loss of cristae structure. FABP5 inhibition in Tregs triggers mtDNA release and consequent cGAS-STING-dependent type I IFN signaling, which induces heightened production of the regulatory cytokine IL-10 and promotes Treg suppressive activity. We find evidence of this pathway, along with correlative mitochondrial changes in tumor infiltrating Tregs, which may underlie enhanced immunosuppression in the tumor microenvironment. Together, our data reveal that FABP5 is a gatekeeper of mitochondrial integrity that modulates Treg function.
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Project description:Although several markers have been associated with the characterization of regulatory T cells (Treg) and their function, no studies have investigated the dynamics of their phenotype during infection. Since the necessity of Treg to control immunopathology has been demonstrated, we used the chronic helminth infection model S. mansoni to address the impact on the Treg gene repertoire. Before gene expression profiling we first chose to study the localization and antigen-specific suppressive nature of classically defined Treg during infection. Presence of Foxp3+ cells were found especially in the periphery of granulomas and isolated CD4+CD25hiFoxp3+ Treg from infected mice blocked IFN-gamma and IL-10 cytokine secretion from infected CD4+CD25- effector T cells (Teff). Furthermore the gene expression patterns of Treg and Teff showed that in total 474 genes were significantly regulated during chronic schistosomiasis. Upon k-means clustering we identified genes exclusively regulated in all four populations including Foxp3, CD103, GITR, OX40 and CTLA-4: classical Treg markers. During infection however, several non-classical genes were up-regulated solely within the Treg population such as Slpi, Gzmb, Mt1, Fabp5, Nfil3, Socs2, Gpr177 and Klrg1. Using RT-PCR we confirmed aspects of the microarray data and in addition showed that the expression profile of Treg from S. mansoni-infected mice is simultaneously unique and comparative with Treg derived from other infections Regulatory T cells (Treg) or effector T cells (Teff) were FACS-sorted as CD4+CD25+ or CD4+CD25- from mesenteric lymph nodes (MLN) of naive mice or from mice infected with Schistosoma mansoni. Affymetrix MOE430A 2.0 genechips were used to identify genes differentially expressed in Treg or Teff under resting or infected conditions.
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Project description:Regulatory T (Treg) cells are crucial for immune homeostasis but they also contribute to tumor immune evasion by promoting a suppressive tumor microenvironment (TME). Mice with Treg cell-restricted Neuropilin 1 deficiency show tumor resistance while maintaining peripheral immune homeostasis, thereby providing a controlled system to interrogate the impact of intratumoral Treg cells on the TME. Using this and other genetic models, we showed that Treg cells shaped the transcriptional landscape across multiple tumor-infiltrating immune cell types. Treg cells suppressed CD8+ T cell secretion of interferon-gamma(IFN[gamma]), which would otherwise block the activation of sterol regulatory element-binding protein 1 (SREBP1)-mediated fatty acid synthesis in immunosuppressive (M2-like) tumor-associated macrophages (TAMs). Thus, Treg cells indirectly but selectively sustained M2-like TAM metabolic fitness, mitochondrial integrity and survival. SREBP1 inhibition augmented the efficacy of immune checkpoint blockade, suggesting that targeting Treg cells or their modulation of lipid metabolism in M2-like TAMs could improve cancer immunotherapy.
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2024-01-11 | GSE236824 | GEO
Project description:Regulatory T (Treg) cells are essential for immune homeostasis but inhibit immune rejection of cancer. Strategies to disrupt Treg-mediated cancer immunosuppression have been met with limited clinical success, but the underlying mechanisms for this failure are poorly understood. By modeling Treg-targeted immunotherapy in mice, we find that a subset of CD4+ Foxp3- conventional T (Tconv) cells with potent suppressive function undergoes activation and expansion upon depletion of Foxp3+ Treg cells and limits therapeutic efficacy. We noted that Foxp3- Tconv cells within tumors adopt a Treg-like transcriptional profile upon Treg depletion and acquire suppressive function. This is attributable to a Th2-like subset of CD4+ Tconv cells marked by expression of (C-C motif) receptor 8 (CCR8) and enriched in Treg-associated transcripts. CCR8+ Tconv cells are found in mouse and human tumors. Upon Treg depletion, CCR8+ Tconv cells undergo systemic and intratumoral activation and expansion, resulting in IL-10 dependent suppression of anti-tumor immunity. Consequently, conditional deletion of Il10 within T cells augments anti-tumor efficacy upon Treg-depletion in mice, and antibody blockade of IL-10 signaling synergizes with Treg depletion to overcome treatment resistance. These findings reveal a secondary layer of immunosuppression by Tconv cells released upon therapeutic Treg depletion and suggest that broader consideration of suppressive function within the T cell lineage is required for development of effective Treg-targeted therapies.
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