Immunosuppressive CD29+ Treg accumulation in the liver in mice upon checkpoint inhibitor therapy
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA913172 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22777640.fastq.gz | Fastqsanger.gz | |||
| SRR22777641.fastq.gz | Fastqsanger.gz | |||
| SRR22777642.fastq.gz | Fastqsanger.gz | |||
| SRR22777643.fastq.gz | Fastqsanger.gz |
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Project description:Regulatory T (Treg) cells, which belong to the CD4 T cell subset, are critical for immunological tolerance and immune homeostasis. Using a combination of RNA-seq and proteome analyses, we found that Acsbg1, a member of ACSL, is selectively expressed in Treg cells. Furthermore, we found that gene loci of Acsbg1 was epigenetically regulated and opened up by Smad2/3 in Treg cells. Deletion of Smad2/3 decreased expression levels of Acsbg1 compared to control T reg cells. We show that the genetic deletion and pharmacological inhibition of Acsbg1 causes not only mitochondrial dysfunction, but also dampens other metabolic pathways including glycolysis and the TCA-cycle. The extrinsic supplementation of sgAcsbg1 Treg cells with oleoyl-CoA restored the phenotype of the Treg metabolic signature. Furthermore, we also found evidence of this pathway in ST2+ effector Treg cells in the lung, which underlies the enhanced immunosuppressive capacity in the airway inflammation. This study provide a framework of Acsbg1 serving as a metabolic checkpoint governing Treg cell homeostasis and the resolution of lung inflammation.
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Project description:ObjectiveLiver metastases are often resistant to immune checkpoint inhibitor therapy (ICI) and portend a worse prognosis compared with metastases to other locations. Regulatory T cells (Tregs) are one of several immunosuppressive cells implicated in ICI resistance of liver tumours, but the role played by Tregs residing within the liver surrounding a tumour is unknown.DesignFlow cytometry and single-cell RNA sequencing were used to characterise hepatic Tregs before and after ICI therapy.ResultsWe found that the murine liver houses a Treg population that, unlike those found in other organs, is both highly proliferative and apoptotic at baseline. On administration of αPD-1, αPD-L1 or αCTLA4, the liver Treg population doubled regardless of the presence of an intrahepatic tumour. Remarkably, this change was not due to the preferential expansion of the subpopulation of Tregs that express PD-1. Instead, a subpopulation of CD29+ (Itgb1, integrin β1) Tregs, that were highly proliferative at baseline, doubled its size in response to αPD-1. Partial and full depletion of Tregs identified CD29+ Tregs as the prominent niche-filling subpopulation in the liver, and CD29+ Tregs demonstrated enhanced suppression in vitro when derived from the liver but not the spleen. We identified IL2 as a critical modulator of both CD29+ and CD29- hepatic Tregs, but expansion of the liver Treg population with αPD-1 driven by CD29+ Tregs was in part IL2-independent.ConclusionWe propose that CD29+ Tregs constitute a unique subpopulation of hepatic Tregs that are primed to respond to ICI agents and mediate resistance.
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Project description:Regulatory T (Treg) cells can facilitate transplant tolerance and attenuate autoimmune- and inflammatory diseases. Therefore, it is clinically relevant to stimulate Treg cell expansion and function in vivo and to create therapeutic Treg cell products in vitro. We report that TNF receptor 2 (TNFR2) is a unique costimulus for naïve, thymus-derived (t)Treg cells from human blood that promotes their differentiation into non-lymphoid tissue (NLT)-resident effector Treg cells, without Th-like polarization. In contrast, CD28 costimulation maintains a lymphoid tissue (LT)-resident Treg cell phenotype. We base this conclusion on transcriptome and proteome analysis of TNFR2- and CD28-costimulated CD4+ Treg cells and conventional T (Tconv) cells, followed by bioinformatic comparison with published transcriptomic Treg cell signatures from NLT and LT in health and disease, including autoimmunity and cancer. These analyses illuminate that TNFR2 costimulation promotes Treg cell capacity for survival, migration, immunosuppression and tissue regeneration. Functional studies confirmed improved migratory ability of TNFR2-costimulated tTreg cells. Flow cytometry validated the presence of the TNFR2-driven Treg cell signature in effector/memory Treg cells from the human placenta as opposed to blood. Thus, TNFR2 can be exploited as driver of NLT-resident Treg cell differentiation for adoptive cell therapy or antibody-based immunomodulation in human disease.
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