Regulatory T Cells and Human Disease

Annual Review of Immunology, Journal Year: 2020, Volume and Issue: 38(1), P. 541 - 566

Published: Feb. 4, 2020

Naturally occurring CD4+ regulatory T cells (Tregs), which specifically express the transcription factor FoxP3 in nucleus and CD25 CTLA-4 on cell surface, are a functionally distinct subpopulation actively engaged maintenance of immunological self-tolerance homeostasis. Recent studies have facilitated our understanding cellular molecular basis their generation, function, phenotypic functional stability, adaptability. It is under investigation humans how or numerical Treg anomalies, whether genetically determined environmentally induced, contribute to diseases such as autoimmune diseases. Also being addressed Tregs can be targeted control physiological pathological immune responses, for example, by depleting them enhance tumor immunity expanding treat This review discusses current immunobiology normal disease states, with perspective realization Treg-targeting therapies clinic.

Language: Английский

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Regulatory T cells in tumor microenvironment: new mechanisms, potential therapeutic strategies and future prospects

Molecular Cancer, Journal Year: 2020, Volume and Issue: 19(1)

Published: July 17, 2020

Abstract Regulatory T cells (Tregs) characterized by the expression of master transcription factor forkhead box protein p3 (Foxp3) suppress anticancer immunity, thereby hindering protective immunosurveillance tumours and hampering effective antitumour immune responses in tumour-bearing hosts, constitute a current research hotspot field. However, Tregs are also essential for maintenance tolerance body share many molecular signalling pathways with conventional cells, including cytotoxic primary mediators tumour immunity. Hence, inability to specifically target neutralize microenvironment without globally compromising self-tolerance poses significant challenge. Here, we review recent advances characterizing tumour-infiltrating focus on functional roles costimulatory inhibitory receptors Tregs, evaluate their potential as clinical targets, systematically summarize treatment strategies. Also, propose modalities integrate our increasing knowledge phenotype function rational design checkpoint inhibitor-based combination therapies. Finally, possible strategies that can be used develop Treg-targeted

Language: Английский

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Mitochondrial complex III is essential for suppressive function of regulatory T cells

Nature, Journal Year: 2019, Volume and Issue: 565(7740), P. 495 - 499

Published: Jan. 1, 2019

Language: Английский

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Genetic Architectures of Childhood- and Adult-Onset Asthma Are Partly Distinct

The American Journal of Human Genetics, Journal Year: 2019, Volume and Issue: 104(4), P. 665 - 684

Published: March 28, 2019

Language: Английский

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NLRP3 Inflammasome Regulates Development of Systemic Inflammatory Response and Compensatory Anti-Inflammatory Response Syndromes in Mice With Acute Pancreatitis

Gastroenterology, Journal Year: 2019, Volume and Issue: 158(1), P. 253 - 269.e14

Published: Oct. 5, 2019

Background & AimsPancreatitis starts with primarily sterile local inflammation that induces systemic inflammatory response syndrome, followed by compensatory anti-inflammatory syndrome (CARS). We investigated the mechanisms of these processes in mice and human serum.MethodsWe induced severe acute pancreatitis partial duct ligation caerulein stimulation or intraperitoneal injection l-arginine deletion interleukin (IL)12B, NLRP3, IL18 given MCC950, a small molecule inhibitor NLRP3-inflammasome. Pancreata were collected from analyzed histology, cytokine levels measured serum samples. activation adaptive immune responses flow cytometry analysis T cells (CD25 CD69) isolated spleen. Differentiation T-helper (Th1) cells, Th2 T-regulatory was determined nuclear staining for TBET, GATA3, FOXP3. performed transcriptome mouse lymph nodes bone marrow–derived macrophages after incubation acini. cytokines samples patients mild pancreatitis.ResultsActivation initiated macrophage-derived, caspase 1–processed required NLRP3 (confirmed pancreatitis). Spleen had increases but not Th1 cells. Bone secreted IL1B IL18, IL12, co-incubation pancreatic T-cell severity did differ significantly between IL12B-deficient control mice. In contrast, NLRP3- IL18-deficient reduced no increase cell–mediated compared The type 2 mediated macrophage-derived IL1 family. Specifically, absence IL12. MCC950 neutrophil infiltration, activation, disease mice.ConclusionsIn pancreatitis, we found developed parallel. Infiltrating promote simultaneously induce via IL18. Inhibition reduces might be used to treat pancreatitis. Pancreatitis serum. Activation

Language: Английский

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Emerging Functions of Regulatory T Cells in Tissue Homeostasis

Frontiers in Immunology, Journal Year: 2018, Volume and Issue: 9

Published: April 25, 2018

CD4+Foxp3+ regulatory T-cells (Tregs) are a unique subset of helper T-cells, which regulate immune response and establish peripheral tolerance. Tregs not only maintain the tone tenor an by dominant tolerance but, in recent years, have also been identified as key players resolving tissue inflammation mediators healing. Apart from being diverse their origin (thymic peripheral) location (lymphoid resident), phenotypically heterogeneous per orientation ongoing response. In this review, we discuss advances field Treg biology general, non-lymphoid tissue-resident particular. We elaborate upon well-known visceral adipose tissue, colon, skin, tumor-infiltrating newly populations lungs, skeletal muscle, placenta, other tissues. Our attempt is to differentiate based on distinctive properties location, origin, ligand specificity, chemotaxis, specific suppressive mechanisms. Despite ever expanding roles maintaining systemic homeostasis, employed large varieties tumors dampen antitumor immunity. Thus, comprehensive understanding context can be instrumental effectively managing transplantation, autoimmunity, responses.

Language: Английский

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Parkinson’s disease patients have a complex phenotypic and functional Th1 bias: cross-sectional studies of CD4+ Th1/Th2/T17 and Treg in drug-naïve and drug-treated patients

Journal of Neuroinflammation, Journal Year: 2018, Volume and Issue: 15(1)

Published: July 12, 2018

Parkinson's disease (PD) affects an estimated 7 to 10 million people worldwide, and only symptomatic treatments are presently available relieve the consequences of brain dopaminergic neurons loss. Neuronal degeneration in PD is consequence neuroinflammation turn influenced by peripheral adaptive immunity, with CD4+ T lymphocytes playing a key role. cells may however acquire proinflammatory phenotypes, such as helper (Th) 1 Th17, well anti-inflammatory Th2 regulatory (Treg) one, what extent different cell subsets imbalanced their functions dysregulated remains largely unresolved issue.We performed two cross-sectional studies antiparkinson drug-treated drug-naïve patients, age- sex-matched healthy subjects. In first we examined circulating Th1, Th2, second one Treg. Number frequency blood were assessed flow cytometry studied ex vivo assays. both studies, complete clinical assessment, count lineage-specific transcription factors mRNA levels independently thereafter compared for consistency.PD patients have reduced lymphocytes, due Naïve from preferentially differentiate towards Th1 lineage. Production interferon-γ tumor necrosis factor-α increased maintained presence homologous This Th1-biased immune signature occurs on drugs, suggesting that current drugs do not affect immunity.The complex phenotypic functional profile strengthen evidence immunity involved PD, represents target preclinical assessment novel immunomodulating therapeutics.

Language: Английский

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Trial watch: TLR3 agonists in cancer therapy

OncoImmunology, Journal Year: 2020, Volume and Issue: 9(1)

Published: Jan. 1, 2020

Toll-like receptor 3 (TLR3) is a pattern recognition that senses exogenous (viral) as well endogenous (mammalian) double-stranded RNA in endosomes. On activation, TLR3 initiates signal transduction pathway culminates with the secretion of pro-inflammatory cytokines including type I interferon (IFN). The latter essential not only for innate immune responses to infection but also initiation antigen-specific immunity against viruses and malignant cells. These aspects biology have supported development various agonists use stand-alone agents or combined other therapeutic modalities cancer patients. Here, we review recent preclinical clinical advances oncological disorders.Abbreviations cDC, conventional dendritic cell; CMT, cytokine modulating treatment; CRC, colorectal carcinoma; CTL, cytotoxic T lymphocyte; DC, dsRNA, RNA; FLT3LG, fms-related tyrosine kinase ligand; HNSCC, head neck squamous cell IFN, interferon; IL, interleukin; ISV, situ vaccine; MUC1, mucin 1, surface associated; PD-1, programmed death 1; PD-L1, death-ligand polyA:U, polyadenylic:polyuridylic acid; polyI:C, polyriboinosinic:polyribocytidylic TLR,

Language: Английский

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Tumor metabolite lactate promotes tumorigenesis by modulating MOESIN lactylation and enhancing TGF-β signaling in regulatory T cells

Cell Reports, Journal Year: 2022, Volume and Issue: 39(12), P. 110986 - 110986

Published: June 1, 2022

Regulatory T (Treg) cells play a vital role in maintaining the immunosuppressive tumor microenvironment. Lactate is crucial metabolite cancer and related to prognosis, metastasis, overall survival. In this study, we focus on effects of lactate Treg cells. vitro, improves cell stability function, whereas degradation reduces induction, increases antitumor immunity, decreases growth mice. Mechanistically, modulates generation through lactylation Lys72 MOESIN, which MOESIN interaction with transforming factor β (TGF-β) receptor I downstream SMAD3 signaling. Cotreatment anti-PD-1 dehydrogenase inhibitor has stronger effect than alone. Individuals hepatocellular carcinoma who responded treatment have lower levels nonresponding individuals. Thus, identify as an essential small molecule that reinforces microenvironment lactylation.

Language: Английский

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What’s Sex Got to Do With COVID-19? Gender-Based Differences in the Host Immune Response to Coronaviruses

Frontiers in Immunology, Journal Year: 2020, Volume and Issue: 11

Published: Aug. 28, 2020

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing the disease 2019 (COVID-19) pandemic has ravaged world, with over 4.5 million cases and 300,000 deaths worldwide as of May 15th 2020. While elderly are most severely affected, implicating an age bias, a striking factor in demographics this deadly is gender higher numbers cases, greater severity death rates among men versus women across lifespan. pre-existing comorbidities, social, behavioral lifestyle factors contribute to biological underlying host immune response crucial contributors. Women mount stronger responses infections vaccination, outlive men. Sex-based therefore important determinants susceptibility infections, outcomes mortality. Yet sorely understudied often overlooked variable research related infectious diseases, largely ignored drug vaccine clinical trials. Understanding these will not only help better understand pathogenesis disease, but also guide design effective therapies strategies for gender-based personalized medicine. This review focuses on sex-based differences genes, sex hormones microbiome their relevance focus Coronaviruses.

Language: Английский

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