scholarly journals Tim3 binding to galectin-9 stimulates antimicrobial immunity

2010 ◽  
Vol 207 (11) ◽  
pp. 2343-2354 ◽  
Author(s):  
Pushpa Jayaraman ◽  
Isabel Sada-Ovalle ◽  
Sarah Beladi ◽  
Ana C. Anderson ◽  
Valerie Dardalhon ◽  
...  
Keyword(s):  
T Cell ◽  
Macrophage Activation ◽  
Th1 Cells ◽  
Th1 Cell ◽  
Cell Surface Molecule ◽  
Tissue Inflammation ◽  
Regulatory Molecule ◽  
Domain 3 ◽  
Antimicrobial Immunity

T cell immunoglobulin and mucin domain 3 (Tim3) is a negative regulatory molecule that inhibits effector TH1-type responses. Such inhibitory signals prevent unintended tissue inflammation, but can be detrimental if they lead to premature T cell exhaustion. Although the role of Tim3 in autoimmunity has been extensively studied, whether Tim3 regulates antimicrobial immunity has not been explored. Here, we show that Tim3 expressed on TH1 cells interacts with its ligand, galectin-9 (Gal9), which is expressed by Mycobacterium tuberculosis–infected macrophages to restrict intracellular bacterial growth. Tim3–Gal9 interaction leads to macrophage activation and stimulates bactericidal activity by inducing caspase-1–dependent IL-1β secretion. We propose that the TH1 cell surface molecule Tim3 has evolved to inhibit growth of intracellular pathogens via its ligand Gal9, which in turn inhibits expansion of effector TH1 cells to prevent further tissue inflammation.

scholarly journals Transcriptomic Analysis of the Effect of GAT-2 Deficiency on Differentiation of Mice Naïve T Cells Into Th1 Cells In Vitro

2021 ◽  
Vol 12 ◽  
Author(s):  
Xueyan Ding ◽  
Yajie Chang ◽  
Siquan Wang ◽  
Dong Yan ◽  
Jiakui Yao ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Janus Kinase ◽  
Cell Mediated Immunity ◽  
Th1 Cells ◽  
Th1 Cell ◽  
Bioinformatics Analyses ◽  
Naive T Cells ◽  
Naïve T Cells

The neurotransmitter γ-aminobutyric acid (GABA) is known to affect the activation and function of immune cells. This study investigated the role of GABA transporter (GAT)-2 in the differentiation of type 1 helper T (Th1) cells. Naïve CD4+ T cells isolated from splenocytes of GAT-2 knockout (KO) and wild-type (WT) mice were cultured; Th1 cell differentiation was induced and transcriptome and bioinformatics analyses were carried out. We found that GAT-2 deficiency promoted the differentiation of naïve T cells into Th1 cells. RNA sequencing revealed 2984 differentially expressed genes including 1616 that were up-regulated and 1368 that were down-regulated in GAT-2 KO cells compared to WT cells, which were associated with 950 enriched Gene Ontology terms and 33 enriched Kyoto Encyclopedia of Genes and Genomes pathways. Notably, 4 signal transduction pathways (hypoxia-inducible factor [HIF]-1, Hippo, phospholipase D, and Janus kinase [JAK]/signal transducer and activator of transcription [STAT]) and one metabolic pathway (glycolysis/gluconeogenesis) were significantly enriched by GAT-2 deficiency, suggesting that these pathways mediate the effect of GABA on T cell differentiation. Our results provide evidence for the immunomodulatory function of GABA signaling in T cell-mediated immunity and can guide future studies on the etiology and management of autoimmune diseases.

scholarly journals The role of uncoupling protein 2 in macrophages and its impact on obesity-induced adipose tissue inflammation and insulin resistance

2020 ◽  
Vol 295 (51) ◽  
pp. 17535-17548
Author(s):  
Xanthe A. M. H. van Dierendonck ◽  
Tiphaine Sancerni ◽  
Marie-Clotilde Alves-Guerra ◽  
Rinke Stienstra
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Macrophage Activation ◽  
Uncoupling Protein ◽  
Uncoupling Protein 2 ◽  
Adipose Tissue Inflammation ◽  
Tissue Inflammation ◽  
Obesity And Diabetes ◽  
Adipose Tissue Macrophages

The development of a chronic, low-grade inflammation originating from adipose tissue in obese subjects is widely recognized to induce insulin resistance, leading to the development of type 2 diabetes. The adipose tissue microenvironment drives specific metabolic reprogramming of adipose tissue macrophages, contributing to the induction of tissue inflammation. Uncoupling protein 2 (UCP2), a mitochondrial anion carrier, is thought to separately modulate inflammatory and metabolic processes in macrophages and is up-regulated in macrophages in the context of obesity and diabetes. Here, we investigate the role of UCP2 in macrophage activation in the context of obesity-induced adipose tissue inflammation and insulin resistance. Using a myeloid-specific knockout of UCP2 (Ucp2ΔLysM), we found that UCP2 deficiency significantly increases glycolysis and oxidative respiration, both unstimulated and after inflammatory conditions. Strikingly, fatty acid loading abolished the metabolic differences between Ucp2ΔLysM macrophages and their floxed controls. Furthermore, Ucp2ΔLysM macrophages show attenuated pro-inflammatory responses toward Toll-like receptor-2 and -4 stimulation. To test the relevance of macrophage-specific Ucp2 deletion in vivo, Ucp2ΔLysM and Ucp2fl/fl mice were rendered obese and insulin resistant through high-fat feeding. Although no differences in adipose tissue inflammation or insulin resistance was found between the two genotypes, adipose tissue macrophages isolated from diet-induced obese Ucp2ΔLysM mice showed decreased TNFα secretion after ex vivo lipopolysaccharide stimulation compared with their Ucp2fl/fl littermates. Together, these results demonstrate that although UCP2 regulates both metabolism and the inflammatory response of macrophages, its activity is not crucial in shaping macrophage activation in the adipose tissue during obesity-induced insulin resistance.

scholarly journals The Rate of CD4 T Cell Entry into the Lungs duringMycobacterium tuberculosisInfection Is Determined by Partial and Opposing Effects of Multiple Chemokine Receptors

2019 ◽  
Vol 87 (6) ◽  
Author(s):  
Stella G. Hoft ◽  
Michelle A. Sallin ◽  
Keith D. Kauffman ◽  
Shunsuke Sakai ◽  
Vitaly V. Ganusov ◽  
...  
Keyword(s):  
T Cell ◽  
Chemokine Receptors ◽  
Average Rate ◽  
Lung Parenchyma ◽  
Cell Entry ◽  
Th1 Cells ◽  
Entry Rate ◽  
Th1 Cell ◽  
Content Type ◽  
T Cell Migration

ABSTRACTThe specific chemokine receptors utilized by Th1 cells to migrate into the lung duringMycobacterium tuberculosisinfection are unknown. We previously showed in mice that CXCR3+Th1 cells enter the lung parenchyma and suppressM. tuberculosisgrowth, while CX3CR1+KLRG1+Th1 cells accumulate in the lung vasculature and are nonprotective. Here we quantify the contributions of these chemokine receptors to the migration and entry rate of Th1 cells intoM. tuberculosis-infected lungs using competitive adoptive transfer migration assays and mathematical modeling. We found that in 8.6 h half ofM. tuberculosis-specific CD4 T cells migrate from the blood to the lung parenchyma. CXCR3 deficiency decreases the average rate of Th1 cell entry into the lung parenchyma by half, while CX3CR1 deficiency doubles it. KLRG1 blockade has no effect on Th1 cell lung migration. CCR2, CXCR5, and, to a lesser degree, CCR5 and CXCR6 also promote the entry of Th1 cells into the lungs of infected mice. Moreover, blockade of G-protein-coupled receptors with pertussis toxin treatment prior to transfer only partially inhibits T cell migration into the lungs. Thus, the fraction of Th1 cell input into the lungs duringM. tuberculosisinfection that is regulated by chemokine receptors likely reflects the cumulative effects of multiple chemokine receptors that mostly promote but that can also inhibit entry into the parenchyma.

scholarly journals Gαq Regulates the Development of Rheumatoid Arthritis by Modulating Th1 Differentiation

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Dashan Wang ◽  
Yuan Liu ◽  
Yan Li ◽  
Yan He ◽  
Jiyun Zhang ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Bone Marrow ◽  
Immune Regulation ◽  
Inflammatory Arthritis ◽  
Mammalian Cells ◽  
Th1 Cells ◽  
Th1 Cell ◽  
Th1 Cytokine ◽  
Negative Role

The Gαq-containing G protein, an important member ofGq/11class, is ubiquitously expressed in mammalian cells. Gαq has been found to play an important role in immune regulation and development of autoimmune disease such as rheumatoid arthritis (RA). However, how Gαq participates in the pathogenesis of RA is still not fully understood. In the present study, we aimed to find out whether Gαq controls RA via regulation of Th1 differentiation. We observed that the expression of Gαq was negatively correlated with the expression of signature Th1 cytokine (IFN-γ) in RA patients, which suggests a negative role of Gαq in differentiation of Th1 cells. By using Gαq knockout (Gnaq−/−) mice, we demonstrated that loss of Gαq led to enhanced Th1 cell differentiation. Gαq negative regulated the differentiation of Th1 cell by modulating the expression of T-bet and the activity of STAT4. Furthermore, we detected the increased ratio of Th1 cells inGnaq−/−bone marrow (BM) chimeras spontaneously developing inflammatory arthritis. In conclusion, results presented in the study demonstrate that loss of Gαq promotes the differentiation of Th1 cells and contributes to the pathogenesis of RA.

TLR agonists induce regulatory dendritic cells to recruit Th1 cells via preferential IP-10 secretion and inhibit Th1 proliferation

Blood ◽  
2006 ◽  
Vol 109 (8) ◽  
pp. 3308-3315 ◽  
Author(s):  
Cheng Qian ◽  
Huazhang An ◽  
Yizhi Yu ◽  
Shuxun Liu ◽  
Xuetao Cao
Keyword(s):  
Cell Proliferation ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Response ◽  
Th1 Cells ◽  
Th1 Cell ◽  
Chemokine Production ◽  
Innate And Adaptive Immunity ◽  
Tlr Agonists ◽  
Tlr Agonist

Abstract Dendritic cells (DCs) and chemokines are important mediators linking innate and adaptive immunity on activation by Toll-like receptor (TLR) agonists. We previously identified a kind of regulatory DC subset (diffDCs) that differentiated from mature DCs under splenic stroma and that inhibited T-cell proliferation. The responsiveness of such regulatory DCs to TLR agonists and their pattern of chemokine production remain to be determined. Here, we report that the regulatory DCs secrete a higher level of CXCR3 chemokine IFN-γ–induced protein-10 (IP-10) than immature DCs (imDCs), and more IP-10 is produced after stimulation with TLR-2, -4, -3, and -9 ligands. Blockade of IFN-α/β inhibits IP-10 production by TLR agonist-activated regulatory DCs. We show that the increased IRF-3 and IFN-β–induced STAT1 activation are responsible for the autocrine IFN-β–dependent preferential production of IP-10 by regulatory DCs. In addition, stimulation with recombinant mouse IFN-α/β induces more IP-10 production in regulatory DCs than that in imDCs. Moreover, the regulatory DCs selectively recruit more Th1 cells through IP-10 and inhibit Th1 proliferation. Our results demonstrate a new manner for regulatory DCs to down-regulate T-cell response by preferential IP-10 production and inhibition of recruited Th1 cell proliferation.

scholarly journals Serine 182 on RORγt regulates T helper 17 and regulatory T cell functions to resolve inflammation

2021 ◽  
Author(s):  
Shengyun Ma ◽  
Shefali Patel ◽  
Nicholas Chen ◽  
Parth R Patel ◽  
Benjamin S Cho ◽  
...  
Keyword(s):  
T Cell ◽  
Treg Cells ◽  
Orphan Receptor ◽  
T Helper 17 ◽  
Autoimmune Encephalomyelitis ◽  
Tissue Inflammation ◽  
Cell Functions ◽  
Autoimmune Conditions ◽  
Delayed Recovery

Unresolved inflammation causes tissue damage and contributes to autoimmune conditions. However, the molecules and mechanisms controlling T cell mediated inflammation remain to be fully elucidated. Here, we report an unexpected role of the RAR-Related Orphan Receptor-gamma protein (RORγt) in resolving tissue inflammation. Single-cell RNA-seq (scRNA-seq) revealed that an evolutionarily conserved serine 182 residue on ROR&γt (RORγtS182) is critical for restricting IL-1β-mediated Th17 activities and promoting anti-inflammatory cytokine IL-10 production in RORγt+ Treg cells in inflamed tissues. Phospho-null RORγtS182A knock-in mice experienced delayed recovery and succumbed to exacerbated diseases after dextran sulfate sodium (DSS) induced colitis and experimental autoimmune encephalomyelitis (EAE) challenge. Together, these results highlight the essential role of ROR&γtS182 in resolving T cell mediated tissue inflammation, providing a potential therapeutic target to combat autoimmune diseases.

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