Loss of CD4+ T cell-intrinsic arginase 1 accelerates Th1 response kinetics and reduces lung pathology during influenza infection
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE214241 | GEO | 2023/08/14
REPOSITORIES: GEO
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Project description:As sufficient extracellular arginine is crucial for T cell function, depletion of extracellular arginine by elevated Arginase 1 (Arg1) activity has emerged as a hallmark immunosuppressive mechanism. However, the potential cell-autonomous roles of arginases in T cells have remained unexplored. Here we show that the arginase isoform expressed by T cells, the mitochondrial Arginase 2 (Arg2), is a cell-intrinsic regulator of CD8+ T cell activity. Both germ-line Arg2 deletion and adoptive transfer of Arg2-/- CD8+ T cells significantly reduced tumor growth in preclinical cancer models by enhancing CD8+ T cell activation, effector function and persistence. Transcriptomic, proteomic and high-dimensional flow cytometry characterization revealed a CD8+ T cell-intrinsic role of Arg2 in modulating T cell activation, anti-tumor cytoxicity and memory formation, independently of extracellular arginine availability. Furthermore, specific deletion of Arg2 in CD8+ T cells strongly synergized with PD-1 blockade for the control of tumor growth and animal survival. These observations coupled with the finding that pharmacologic arginase inhibition accelerates activation of ex vivo human T cells unveil Arg2 as a new therapeutic target for T cell-based cancer therapies.
2019-11-02 | GSE139811 | GEO
Project description:Brain myeloid cells, include infiltrating macrophages and resident microglia, play an essential role in responding to and inducing neurodegenerative diseases, such as Alzheimer’s disease (AD). Genome-wide association studies (GWAS) implicate many AD casual and risk genes enriched in brain myeloid cells. Coordinated arginine metabolism through arginase 1 (Arg1) is critical for brain myeloid cells to perform biological functions, whereas dysregulated arginine metabolism disrupts them. Altered arginine metabolism is proposed as a new biomarker pathway for AD. We previously reported Arg1 deficiency in myeloid biased cells using lysozyme M (LysM) promoter-driven deletion worsened amyloidosis-related neuropathology and behavioral impairment. However, it remains unclear how Arg1 deficiency in these cells impacts the whole brain to promote amyloidosis. Herein, we aim to determine how Arg1 deficiency driven by LysM restriction during amyloidosis affects fundamental neurodegenerative pathways at the transcriptome level. By applying several bioinformatic tools and analyses, we found that amyloid-β (Aβ) stimulated transcriptomic signatures in autophagy-related pathways and myeloid cells' inflammatory response. At the same time, myeloid Arg1 deficiency during amyloidosis promoted gene signatures of lipid metabolism, myelination, and migration of myeloid cells. Focusing on Aβ associated glial transcriptomic signatures, we found myeloid Arg1 deficiency up-regulated glial gene transcripts that positively correlated with Aβ plaque burden. We also observed that Aβ preferentially activated disease-associated microglial signatures to increase phagocytic response, whereas myeloid Arg1 deficiency selectively promoted homeostatic microglial signature that is non-phagocytic. These transcriptomic findings suggest a critical role for proper Arg1 function during normal and pathological challenges associated with amyloidosis. Furthermore, understanding pathways that govern Arg1 metabolism may provide new therapeutic opportunities to rebalance immune function and improve microglia/macrophage fitness.
2021-04-15 | GSE172108 | GEO
Project description:Activated T cells differentiate into functional subsets which require distinct metabolic programs. Glutaminase (GLS) converts glutamine to glutamate to provide substrate for the tricarboxylic acid cycle and epigenetic reactions and here we identify a key role for GLS in T cell activation and specification. Though GLS-deficiency diminished T cell activation, proliferation and impaired differentiation of Th17 cells, loss of GLS also increased Tbet and Interferon-γ expression and CD4 Th1 and CD8 CTL effector cell differentiation. These changes were mediated by differentially altered gene expression and chromatin accessibility, leading to increased sensitivity of Th1 cells to IL-2 mediated mTORC1 signaling. In vivo, GLS-null T cells failed to drive a Th17 mediated Graft-vs-Host Disease model. Transient inhibition of GLS, however, increased Th1 and CTL T cell numbers in viral and chimeric antigen receptor models. Glutamine metabolism thus has distinct roles to promote Th17 but constrain Th1 and CTL effector cell differentiation.
2018-09-01 | E-MTAB-6648 | biostudies-arrayexpress
Project description:Deficiency of arginase is associated with hyperargininemia, and unlike the other disorders of the urea cycle, the major mechanism of metabolism of nitrogen in terrestrial mammals, are characteristic and prominent features that include spastic diplegia/tetraplegia, clonus, and hyperreflexia; loss of ambulation, intellectual disability and progressive neurological decline are other signs. To gain greater insight into the unique neuromotor features, we performed gene expression profiling of the motor cortex of a well-characterized murine model of the disorder. Co-expression network analysis suggested an abnormality with myelination, which was supported by limited existing human data. Utilizing electron microscopy, marked dysmyelination was detected in 2-week-old homozygous ARG1 knockout mice. The corticospinal tract was found to be adversely affected, supporting dysmyelination as the cause of the unique neuromuscular features and implicating oligodendrocyte impairment in a deficiency of hepatic ARG1. Following neonatal hepatic gene therapy to express ARG1, the subcortical white matter, pyramidal tract, and corticospinal tract all showed a remarkable recovery in terms of myelinated axon density and ultrastructural integrity with active wrapping of axons by nearby oligodendrocyte processes. These findings support the following conclusions: first, arginase deficiency is a leukodystrophy affecting the brain and spinal cord while sparing the peripheral nervous system; and second, neonatal AAV hepatic gene therapy can rescue the defects associated with myelinated axons, strongly implicating the functional recovery of oligodendrocytes after restoration of hepatic arginase activity. These findings support the consideration of early restoration of hepatic arginase activity in those afflicted with arginase deficiency.
2019-06-01 | GSE132058 | GEO
Project description:<p>The classic neurotransmitter gamma-aminobutyric acid (GABA) has been shown to shape the activation and function of immune cells. There are four high affinity GABA transporters (GATs, including GAT-1, GAT-2, GAT-3 and GAT-4) responsible for the transmembrane transport of GABA in mice. To explore the effect of GAT-2 on type 1 helper T (Th1) cells, naïve CD4+ T cells were isolated from splenocytes of GAT-2 knockout (KO) and wild-type (WT) mice and cultured for Th1 cell differentiation, and then metabolomics analysis of Th1 cells was performed via gas chromatography coupled to time-of-flight mass spectrometry (GC-TOF-MS) added with multivariate analyses. The study will provide insights into T cell response to GAT-2 deficiency in mice.</p>
2021-10-14 | MTBLS3358 | MetaboLights
Project description:Activated T cells differentiate into functional subsets which require distinct metabolic programs. Glutaminase (GLS) converts glutamine to glutamate to provide substrate for the tricarboxylic acid cycle and epigenetic reactions and here we identify a key role for GLS in T cell activation and specification. Though GLS-deficiency diminished T cell activation, proliferation and impaired differentiation of Th17 cells, loss of GLS also increased Tbet and Interferon-γ expression and CD4 Th1 and CD8 CTL effector cell differentiation. These changes were mediated by differentially altered gene expression and chromatin accessibility, leading to increased sensitivity of Th1 cells to IL-2 mediated mTORC1 signaling. In vivo, GLS-null T cells failed to drive a Th17-mediated Graft-vs-Host Disease model. Transient inhibition of GLS, however, increased Th1 and CTL T cell numbers in viral and chimeric antigen receptor models. Glutamine metabolism thus has distinct roles to promote Th17 but constrain Th1 and CTL effector cell differentiation.
2019-02-13 | GSE112244 | GEO
Project description:Microglia (MG) and macrophages (MPs) represent a significant component of the inflammatory response to gliomas. When activated, MG/MP release a variety of pro-inflammatory cytokines, however, they also secrete anti-inflammatory factors that limit their cytotoxic function. The balance between pro and anti-inflammatory functions dictates their antitumor activity. To evaluate potential variations in MG and MP function in gliomas, we isolated these cells (and other Gr1+ cells) from intracranial GL261 murine gliomas by FACS and evaluated their gene expression profiles by microarray analysis. As expected, arginase 1 (Arg1, M2 marker) was highly expressed by tumor-associated Gr1+, MG and MP. However, in contrast to MP and Gr1+ cells that expressed Arg1 shortly after tumor trafficking, Arg1 expression in MG was delayed and occurred in larger tumors. Interestingly, depletion of MPs in tumors did not prevent MG polarization, suggesting direct influence of tumor-specific factors on MG Arg1 upregulation. Finally, Arg1 expression was confirmed in human GBM samples, but most Arg1+ cells were neutrophils and not MPs. These findings confirm variations in tumor MG and MP polarization states and its dependency on tumor microenvironmental factors.
2016-12-31 | GSE77208 | GEO
Project description:A favourable immunotherapeutic strategy in the treatment of chronic inflammatory disease, is to dampen the pro-inflammatory macrophage response and upregulate the anti-inflammatory macrophage response. Previous studies have shown that Arginase-2 (Arg2), a mitochondrial enzyme, is a key regulator of the macrophage anti-inflammatory response with an essential role in IL-10 signalling. Here we show that IL-10 in the presence of LPS increased Arg2 expression in human macrophages and peripheral blood mononuclear cells. Target site blockers (TSBs) (locked nucleic acid antisense oligonucleotides) specifically designed to target the 3’ UTR of Arg2 messenger RNA were used to inhibit binding of specific microRNAs thus enhancing Arg2 expression. Eleven Arg2-TSBs were screened and the TSB targeting miR-155 (TSB-155) and the TSB targeting miR-3202 (TSB-3202) were found to increase Arg2 expression in human macrophages resulting in decreased gene expression and cytokine production of TNF-α and CCL2. In addition, following TSB-3202 stimulation, there were statistically significant increases in the ‘M2-like’ macrophage marker, CD206; and CD16, associated with an IL-10 response, and a decrease in the ‘M1-like’ macrophage marker, HLA-DR, indicating a shift in the macrophage phenotype. Proteomic analysis demonstrated that multiple pro-inflammatory responsive proteins including Signal Transducer and Activator of Transcription 1 (STAT-1), Toll-like receptors, Signalling Lymphocytic Activation Molecule F7 (SLAMF7) and Interferon Induced Protein with Tetratricopeptide Repeats 3 (IFIT3), were downregulated by TSB-155 and TSB-3202 while Sequestomsome-1 (SQSTM1) was increased after treatment. In silico analysis of significantly dysregulated proteins predicted that TSB-3202 supressed several upstream pro-inflammatory regulators including STAT-1 and Interferon α2 (IFNA2) while enhancing anti-inflammatory associated interleukin 1 receptor antagonist (IL1RN) and STAT-3. Proteomic data was validated by confirming increased levels of SQSTM1, decreased levels of phosphoylated-STAT-1 and STAT-1, and downregulation of Ifit3 and Slamf7 by TSB treatment. In conclusion, upregulation of Arg2 protein by TSBs inhibits several pro-inflammatory signalling proteins resulting in reduced pro-inflammatory cytokine secretion, reduced ‘M1-like’ marker expression and enhanced ‘M2-like’ macrophage marker expression. Arg2 is a promising novel therapeutic target to modulate inflammatory signalling in macrophages.
2023-10-24 | PXD035018 | Pride
Project description:Arginase 1 (Arg1), which converts L-arginine into ornithine and urea, exerts pleiotropic immunoregulatory effects. Patients with inflammatory bowel disease (IBD) show an enhanced expression and activity of Arg1 in the intestinal (sub-)mucosa, but the function of Arg1 in IBD remains poorly characterized. Here, we found that Arg1 expression correlates with the degree of inflammation in colitic tissues of IBD patients. In mice with - experimental colitis Arg1 was upregulated in an IL-4-/IL-13- and intestinal microbiota-dependent manner. Tie2-Cre+/-Arg1fl/fl mice lacking Arg1 in hematopoietic and endothelial cells recovered faster from colitis than Arg1-expressing littermates. This correlated with decreased vessel density, compositional changes in the intestinal microbiota, diminished infiltration by myeloid cellsand an accumulation of intraluminal polyamines that are associated with epithelial healing. Dietary L-arginine restriction abolished the protective effect of Arg1-deletion, suggesting that protection is related to an increased availability of L-arginine. Fecal microbiota transfers from Tie2-Cre+/-Arg1fl/fl mice into wildtype recipients restored the protective, anti-inflammatory phenotype while transfers from wildtype littermates into Arg1-deficient mice prevented the accelerated recovery from colitis. Thus, altered intestinal microbiota and metabolic products in Tie2-Cre+/-Arg1fl/fl mice account for the accelerated resolution from colitis in the absence of Arg1. Subsequently, L-arginine serves as novel therapeutic and diagnostic target for clinical intervention in IBD patients.
2020-06-07 | GSE151931 | GEO
Project description:The tumor microenvironment (TME) contains various immune-suppressive cells such as regulatory T cells (Tregs) and M2-like tumor associated macrophages (TAMs) that express the enzyme arginase I (Arg1). T helper 1-polarized Treg (Th1-Treg) is a Treg subset that markedly accumulate in tumor tissues, suppressing anti-tumor immunity. However, little is known about the mechanism behind the abundant presence of Th1-Tregs in TME. Here we show that Arg1-expressing TAMs (Arg1+ TAMs) play critical roles for the high Th1-Treg ratio in TME. Selective depletion of Arg1+ TAMs using the VeDTR system inhibited tumor growth and concurrently reduced the Th1-Treg ratio in TME. Notably, Arg1+ TAMs secreted platelet factor 4 (PF4) that polarized Tregs to Th1-Tregs in a CXCR3-dependent manner. Both genetic PF4 inactivation and PF4 neutralization hindered Th1-Treg accumulation in TME, consequently suppressing tumor growth. Collectively, our study highlights the importance of M2-like TAM-produced PF4 for high Th1-Treg levels in TME to suppress anti-tumor immunity, and demonstrates PF4 neutralization as a potential cancer immunotherapeutic strategy by intervening the M2-like TAM/Th1-Treg axis.
2024-11-07 | GSE251735 | GEO