Double Negative T Cells Downregulate Intrahepatic Inflammation and Ameliorate Hepatic Ischemia and Reperfusion Injury via CD39-adenosinergic axis [RNA-seq]
Ontology highlight
ABSTRACT: Converted double negative T cells (cDNT) highly express CD39 and hydrolyze ATP into adenosine. ATP/adenosine derived purinergic signaling plays a critical role in immune regulation. However, the role and mechanisms of ATP/adenosine in cDNT is unclear.
Project description:Converted double negative T cells (cDNT) highly expressed ATP hydrolytic enzyme CD39 and hydrolyzed extracellular ATP (eATP) into adenosine. We found that adenosine upregulated the transcription factor FOXO1 expression in cDNT. CUT&Tag assay was performed to investigate the FOXO1 binding promoter sites in cDNT.
Project description:Microglia and the border-associated macrophages contribute to the modulation of cerebral blood flow, but the mechanisms have remained uncertain. Here, we show that microglia regulate the cerebral blood flow baseline and the responses to whisker stimulation or intra-cisternal magna injection of adenosine triphosphate, but not intra-cisternal magna injection of adenosine in mice model. Notably, microglia repopulation corrects these cerebral blood flow anomalies. The microglial-dependent regulation of cerebral blood flow requires the adenosine triphosphate-sensing P2RY12 receptor and ectonucleotidase CD39 that initiates the dephosphorylation of extracellular adenosine triphosphate into adenosine in both male and female mice. Pharmacological inhibition or CX3CR1-CreER-mediated deletion of CD39 mimics the cerebral blood flow anomalies in microglia-deficient mice and reduces the upsurges of extracellular adenosine following whisker stimulation. Together, these results suggest that the microglial CD39-initiated breakdown of extracellular adenosine triphosphate co-transmitter is an important step in neurovascular coupling and the regulation of cerebrovascular reactivity.
Project description:Double Negative T Cells Downregulate Intrahepatic Inflammation and Ameliorate Hepatic Ischemia and Reperfusion Injury via CD39-adenosinergic axis
Project description:Uterine NK cells (uNK cells) form a distinct immune cell population in the endometrium and decidua. Here, we FACS-sorted KIR-CD39-,KIR+CD39- and KIR+CD39+ uNK cells from decidual samples.
Project description:Exhausted T cells express multiple co-inhibitory molecules that impair their function and limit immunity to chronic viral infection. Defining novel markers of exhaustion is important both for identifying and potentially reversing T cell exhaustion. Herein, we show that the ectonucleotidse CD39 is a marker of exhausted CD8+ T cells. CD8+ T cells specific for HCV or HIV express high levels of CD39, but those specific for EBV and CMV do not. CD39 expressed by CD8+ T cells in chronic infection is enzymatically active, co-expressed with PD-1, marks cells with a transcriptional signature of T cell exhaustion and correlates with viral load in HIV and HCV. In the mouse model of chronic Lymphocytic Choriomeningitis Virus infection, virus-specific CD8+ T cells contain a population of CD39high CD8+ T cells that is absent in functional memory cells elicited by acute infection. This CD39high CD8+ T cell population is enriched for cells with the phenotypic and functional profile of terminal exhaustion. These findings provide a new marker of T cell exhaustion, and implicate the purinergic pathway in the regulation of T cell exhaustion. CD8+ T cells from subjects with HCV infection were sorted and pelleted and re-suspended in TRIzol (Invitrogen). RNA extraction was performed using the RNAdvance Tissue Isolation kit (Agencourt). Concentrations of total RNA were determined with a Nanodrop spectrophotometer or Ribogreen RNA quantification kits (Molecular Probes/Invitrogen). RNA purity was determined by Bioanalyzer 2100 traces (Agilent Technologies). Total RNA was amplified with the WT-Ovation Pico RNA Amplification system (NuGEN) according to the manufacturer's instructions. After fragmentation and biotinylation, cDNA was hybridized to HG-U133A 2.0 microarrays (Affymetrix).
Project description:Microglia tightly interact with brain capillaries and regulate blood brain barrel permeability in pathological conditions. However, it is still unknown whether and how microglia regulate CBF in homeostatic condition. Here we show microglia directly regulate cerebral blood flow (CBF) and neurovascular coupling. Conditional knockout of microglial CD39 resulted in CBF hyper perfusion, reduced ATP induced CBF increase, impaired neurovascular coupling by whisker stimulation and reduced whisker stimulation induced adenosine increase in barrel cortex. Out data suggest that microglia is an important player for CBF regulation.
Project description:Double Negative T Cells Downregulate Intrahepatic Inflammation and Ameliorate Hepatic Ischemia and Reperfusion Injury via CD39-adenosinergic axis [ChIP-seq]
Project description:Double Negative T Cells Downregulate Intrahepatic Inflammation and Ameliorate Hepatic Ischemia and Reperfusion Injury via CD39-adenosinergic axis [RNA-seq]
Project description:This is a phase 1/1b study of TTX-030 in combination therapy, an antibody that inhibits CD39 enzymatic activity, leading to accumulation of pro-inflammatory adenosine triphosphate (ATP) and reduction of immunosuppressive adenosine, which may change the tumor microenvironment and promote anti-tumor immune response.
This trial will study the safety, tolerability, pharmacokinetics, pharmacodynamics and anti-tumor activity of TTX-030 in combination with immunotherapy and/or standard chemotherapies.