scholarly journals In Vitro Treg Immunosuppression Assay of GITR Proteins Could Elucidate the Autoimmune-mediated Mechanism Underlying Type 1 Narcolepsy

2021 ◽  
Vol 2 (1) ◽  
pp. 168-178
Author(s):  
Yi-Hsiang Cheng ◽  
Marie Gadziola
Keyword(s):  
Lateral Hypothalamus ◽  
T Regulatory Cells ◽  
Adaptive Immune System ◽  
Treg Cells ◽  
Neuronal Population ◽  
T Regulatory Cell ◽  
Adequate Knowledge ◽  
Hypocretin 1

Abstract: Type 1 narcolepsy is a hypersomnia sleep disorder characterized by excessive daytime sleep and shallow NREM nighttime sleep. Deficiency of hypocretin-1 secreting neurons in the lateral hypothalamus is the primary cause of the disorder and studies demonstrated that these neurons were solely diminished in a brain region of remarkable heterogeneous neuronal population. Specific destruction of targeted neurons could be achieved via antigen presentation to immune cells, a characteristic of cell-mediated response in the adaptive immune system. Given that hypocretin-1 neurons were exclusively targeted, this cultivated significant interest in searching for an autoimmune-mediated mechanism but studies currently lack adequate knowledge and consistent results. In this research proposal, it is hypothesized that enhanced glucocorticoid-induced TNFR-related (GITR) protein expression in T regulatory (Treg) cells results in defective suppression capacity of CD4+CD25+ T helper cells and defective self-tolerance thereby promoting destruction of hypocretin-1 secreting-neurons in the lateral hypothalamus of narcoleptics. The proposal devises a correlational study to measure cerebrospinal fluid (CSF) hypocretin-1 levels that were inversely proportional to GITR expression levels in Treg cells to assess the autoimmune nature of the disorder. This study is aimed at investigating how defective T regulatory cells respond in type 1 narcolepsy patients via CSF hypocretin-1 measurement and in vitro human T regulatory cell suppression assay.

scholarly journals Neither Primary nor Memory Immunity to Mycobacterium tuberculosis Infection Is Compromised in Mice with Chronic Enteric Helminth Infection

2015 ◽  
Vol 83 (3) ◽  
pp. 1217-1223 ◽  
Author(s):  
Wasiulla Rafi ◽  
Kamlesh Bhatt ◽  
William C. Gause ◽  
Padmini Salgame
Keyword(s):  
Mycobacterium Tuberculosis ◽  
T Regulatory Cells ◽  
Helminth Infection ◽  
Treg Cells ◽  
Helminth Species ◽  
Nippostrongylus Brasiliensis ◽  
T Regulatory Cell ◽  
Chronic Infections ◽  
Mycobacterium Tuberculosis Infection ◽  
Content Type

Previously we had reported thatNippostrongylus brasiliensis, a helminth with a lung migratory phase, affected host resistance againstMycobacterium tuberculosisinfection through the induction of alternatively activated (M2) macrophages. Several helminth species do not have an obligatory lung migratory phase but establish chronic infections in the host that include potent immune downregulatory effects, in part mediated through induction of a FoxP3+T regulatory cell (Treg) response. Treg cells exhibit duality in their functions in host defense againstM. tuberculosisinfection since their depletion leads to enhanced priming of T cells in the lymph nodes and attendant improved control ofM. tuberculosisinfection, while their presence in the lung granuloma protects against excessive inflammation.Heligmosomoides polygyrusis a strictly murine enteric nematode that induces a strong FoxP3 Treg response in the host. Therefore, in this study we investigated whether host immunity toM. tuberculosisinfection would be modulated in mice with chronicH. polygyrusinfection. We report that neither primary nor memory immunity conferred byMycobacterium bovisBCG vaccination was affected in mice with chronic enteric helminth infection, despite a systemic increase in FoxP3+T regulatory cells. The findings indicate that anti-M. tuberculosisimmunity is not similarly affected by all helminth species and highlight the need to consider this inequality in human coinfection studies.

scholarly journals Complementary Roles of GCN5 and PCAF in Foxp3+ T-Regulatory Cells

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 554 ◽  
Author(s):  
Yujie Liu ◽  
Chunrong Bao ◽  
Liqing Wang ◽  
Rongxiang Han ◽  
Ulf H. Beier ◽  
...  
Keyword(s):  
Cell Biology ◽  
T Regulatory Cells ◽  
Treg Cells ◽  
Epigenetic Therapy ◽  
Lymphoid Tissues ◽  
Allograft Survival ◽  
Associated Factor ◽  
General Importance

Functions of the GCN5-related N-acetyltransferase (GNAT) family of histone/protein acetyltransferases (HATs) in Foxp3+ T-regulatory (Treg) cells are unexplored, despite the general importance of these enzymes in cell biology. We now show that two prototypical GNAT family members, GCN5 (general control nonrepressed-protein 5, lysine acetyltransferase (KAT)2a) and p300/CBP-associated factor (p300/CBP-associated factor (PCAF), Kat2b) contribute to Treg functions through partially distinct and partially overlapping mechanisms. Deletion of Gcn5 or PCAF did not affect Treg development or suppressive function in vitro, but did affect inducible Treg (iTreg) development, and in vivo, abrogated Treg-dependent allograft survival. Contrasting effects were seen upon targeting of each HAT in all T cells; mice lacking GCN5 showed prolonged allograft survival, suggesting this HAT might be a target for epigenetic therapy in allograft recipients, whereas transplants in mice lacking PCAF underwent acute allograft rejection. PCAF deletion also enhanced anti-tumor immunity in immunocompetent mice. Dual deletion of GCN5 and PCAF led to decreased Treg stability and numbers in peripheral lymphoid tissues, and mice succumbed to severe autoimmunity by 3–4 weeks of life. These data indicate that HATs of the GNAT family have contributions to Treg function that cannot be replaced by the functions of previously characterized Treg HATs (CBP, p300, and Tip60), and may be useful targets in immuno-oncology.

A Commitment to Lineage

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. SCI-22-SCI-22
Author(s):  
Laurie H. Glimcher ◽  
Vanja Lazarevic ◽  
Joerg Ermann ◽  
Wendy Garrett
Keyword(s):  
Colorectal Cancer ◽  
Immune System ◽  
Molecular Mechanisms ◽  
T Regulatory Cells ◽  
Inflammatory Diseases ◽  
Rectal Adenocarcinoma ◽  
Adaptive Immune System ◽  
T Helper ◽  
T Helper 1

Abstract Abstract SCI-22 The transcription factor T-bet, isolated in our laboratory a decade ago, is a master regulator of Type 1 immunity in cells of both the adaptive and innate immune system. In adaptive immunity, T-bet instigates genetic programs in T helper 1 (Th1) cells and is required for production of the hallmark Th1 cytokine IFNg. It simultaneously represses the differentiation of T helper 2 cells and the profibrotic cytokines IL-13 and TGFb. We have recently determined that T-bet is also a repressor of the Th17 genetic program and have established the molecular mechanisms that underpin that function. T-bet also controls the optimal differentiation and function of the cytolytic CD8 cell, and is required for the development of the natural killer T cell. T-bet deficient animals are largely protected from autoimmune/inflammatory diseases such as multiple sclerosis, systemic lupus, type 1 diabetes and inflammatory arthritis, but are susceptible to type 2 driven diseases such as asthma and scleroderma. An exception to this overall rule is our recent discovery that in the absence of an adaptive immune system, the majority of mice lacking T-bet develop a spontaneous ulcerative colitis that progresses to colonic dysplasia and rectal adenocarcinoma. This colitis and inflammation associated colorectal cancer are MyD88 independent, driven by colitogenic flora and ameliorated by treatment with TNF blockade, antibiotics, and transfer of T regulatory cells. This phenotype maps to the T-bet deficient dendritic cell that drives this pro-inflammatory program; selective over-expression of T-bet in DCs was sufficient to reduce colonic inflammation and prevent the progression to neoplasia. The molecular pathogenesis of TRUC colitis and colitis-associated colorectal (caCRC) shares several key features with human caCRC. This model of colitis and colitis-associated colorectal cancer provides opportunities to further understand host-microbial relationships in inflammation and neoplasia and test preventative and therapeutic strategies pre-clinically. The function and mechanism of action of T-bet in the pathogenesis of immune system driven diseases will be discussed. Disclosures: Glimcher: Merck: Consultancy, Patents & Royalties, Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

Generation of T Regulatory Cells in Children with Newly Diagnosed Type 1 Diabetes Mellitus

2011 ◽  
Vol 120 (02) ◽  
pp. 101-109 ◽  
Author(s):  
W. Łuczyński ◽  
N. Wawrusiewicz-Kurylonek ◽  
A. Szypowska ◽  
E. Iłendo ◽  
A. Bossowski ◽  
...  
Keyword(s):  
Gene Expression ◽  
Diabetes Mellitus ◽  
T Regulatory Cells ◽  
Mrna Level ◽  
Treg Cells ◽  
Newly Diagnosed ◽  
Regulatory Cells ◽  
Proliferation Assays ◽  
And Control

AbstractThere is increasing evidence that T-regulatory (Treg) cells could be used to prevent or cure autoimmune diseases including type 1 diabetes mellitus (T1DM). The aim of the present study was to verify the hypothesis that functional Treg cells can be generated from conventional T-cells separated from a small amount of peripheral blood of children with newly diagnosed T1DM (N=25).CD4+CD25- cells were cultured with Treg expander (CD3/CD28) and IL-2 for generating de novo Treg cells. The assessment of the expression of selected genes and proteins critical to Treg function and the proliferation assays were performed with the use of real-time RT-PCR and flow cytometry.After a 4-week stimulation with Treg expander and IL-2, the percentage of T-regulatory cells was significantly higher compared to the cells treated with medium alone (with no difference between diabetic and control children). However, we found some disturbances in the gene expression at mRNA level for molecules crucial for T-reg function. The induced Tregs from diabetic and control children were fully functional as assessed in proliferation assays.despite some disturbances at mRNA level in the critical gene expression, the suppressive properties of induced Treg cells from diabetic and control children were effective.

scholarly journals Factor V is an immune inhibitor that is expressed at increased levels in leukocytes of patients with severe Covid-19

2021 ◽  
Author(s):  
Jun Wang ◽  
Prasanti Kotagiri ◽  
Paul A Lyons ◽  
Federica Mescia ◽  
Laura Bergamaschi ◽  
...  
Keyword(s):  
T Cell ◽  
T Regulatory Cells ◽  
Adaptive Immune System ◽  
Factor V ◽  
Adaptive Immune ◽  
Thrombin Cleavage ◽  
Increased Risk ◽  
Plasma Factor ◽  
T Cell Lymphopenia

AbstractSevere Covid-19 is associated with elevated plasma Factor V (FV) and increased risk of thromboembolism. We report that neutrophils, T regulatory cells (Tregs), and monocytes from patients with severe Covid-19 express FV, and expression correlates with T cell lymphopenia. In vitro full length FV, but not FV activated by thrombin cleavage, suppresses T cell proliferation. Increased and prolonged FV expression by cells of the innate and adaptive immune systems may contribute to lymphopenia in severe Covid-19. Activation by thrombin destroys the immunosuppressive properties of FV. Anticoagulation in Covid-19 patients may have the unintended consequence of suppressing the adaptive immune system.

scholarly journals Localized Th1-, Th2-, T Regulatory Cell-, and Inflammation-Associated Hepatic and Pulmonary Immune Responses in Ascaris suum-Infected Swine Are Increased by Retinoic Acid

2009 ◽  
Vol 77 (6) ◽  
pp. 2576-2587 ◽  
Author(s):  
Harry Dawson ◽  
Gloria Solano-Aguilar ◽  
Madeline Beal ◽  
Ethiopia Beshah ◽  
Vandana Vangimalla ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Alveolar Macrophages ◽  
Molecular Mechanisms ◽  
Corn Oil ◽  
Ascaris Suum ◽  
Treg Cells ◽  
Interleukin 4 ◽  
High Dose ◽  
T Regulatory Cell

ABSTRACT Pigs infected with Ascaris suum or controls were given 100 μg (low-dose) or 1,000 μg (high-dose) all-trans retinoic acid (ATRA)/kg body weight in corn oil or corn oil alone per os on days after inoculation (DAI) −1, +1, and +3 with infective eggs. Treatment with ATRA increased interleukin 4 (IL4) and IL12p70 in plasma of infected pigs at 7 DAI and augmented bronchoalveolar lavage (BAL) eosinophilia observed at 7 and 14 DAI. To explore potential molecular mechanisms underlying these observations, a quantitative real-time reverse transcription (RT)-PCR array was used to examine mRNA expression in tissue. Ascaris-infected pigs had increased levels of liver mRNA for T-helper-2 (Th2)-associated cytokines, mast cell markers, and T regulatory (Treg) cells, while infected pigs given ATRA had higher IL4, IL13, CCL11, CCL26, CCL17, CCL22, and TPSB1 expression. Gene expression for Th1-associated markers (IFNG, IL12B, and TBX21), the CXCR3 ligand (CXCL9), IL1B, and the putative Treg marker TNFRSF18 was also increased. Expression of IL4, IL13, IL1B, IL6, CCL11, and CCL26 was increased in the lungs of infected pigs treated with ATRA. To determine a putative cellular source of eosinophil chemoattractants, alveolar macrophages were treated with IL4 and/or ATRA in vitro. IL4 induced CCL11, CCL17, CCL22, and CCL26 mRNA, and ATRA increased the basal and IL4-stimulated expression of CCL17 and CCL22. Thus, ATRA augments a diverse Th1-, Th2-, Treg-, and inflammation-associated response in swine infected with A. suum, and the increased BAL eosinophilia may be related to enhanced induction of eosinophil chemokine activity by alveolar macrophages.

scholarly journals Low frequency of GITR+ T cells in ex vivo and in vitro expanded Treg cells from type 1 diabetic patients

2013 ◽  
Vol 25 (10) ◽  
pp. 563-574 ◽  
Author(s):  
Cristina Xufré ◽  
Manuela Costa ◽  
Carme Roura-Mir ◽  
Eva Codina-Busqueta ◽  
Lorena Usero ◽  
...  
Keyword(s):  
T Cells ◽  
Ex Vivo ◽  
Low Frequency ◽  
Treg Cells ◽  
Diabetic Patients ◽  
Type 1 Diabetic Patients

scholarly journals Differentiation of type 1 T regulatory cells (Tr1) by tolerogenic DC-10 requires the IL-10–dependent ILT4/HLA-G pathway

Blood ◽  
2010 ◽  
Vol 116 (6) ◽  
pp. 935-944 ◽  
Author(s):  
Silvia Gregori ◽  
Daniela Tomasoni ◽  
Valentina Pacciani ◽  
Miriam Scirpoli ◽  
Manuela Battaglia ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
T Regulatory Cells ◽  
Interleukin 10 ◽  
Regulatory Cells ◽  
Hla Dr ◽  
Human Dendritic Cells ◽  
Tr1 Cells

Abstract Type 1 T regulatory (Tr1) cells suppress immune responses in vivo and in vitro and play a key role in maintaining tolerance to self- and non–self-antigens. Interleukin-10 (IL-10) is the crucial driving factor for Tr1 cell differentiation, but the molecular mechanisms underlying this induction remain unknown. We identified and characterized a subset of IL-10–producing human dendritic cells (DCs), termed DC-10, which are present in vivo and can be induced in vitro in the presence of IL-10. DC-10 are CD14+, CD16+, CD11c+, CD11b+, HLA-DR+, CD83+, CD1a−, CD1c−, express the Ig-like transcripts (ILTs) ILT2, ILT3, ILT4, and HLA-G antigen, display high levels of CD40 and CD86, and up-regulate CD80 after differentiation in vitro. DC-10 isolated from peripheral blood or generated in vitro are potent inducers of antigen-specific IL-10–producing Tr1 cells. Induction of Tr1 cells by DC-10 is IL-10–dependent and requires the ILT4/HLA-G signaling pathway. Our data indicate that DC-10 represents a novel subset of tolerogenic DCs, which secrete high levels of IL-10, express ILT4 and HLA-G, and have the specific function to induce Tr1 cells.

scholarly journals Diminished expression of ICOS, GITR and CTLA-4 at the mRNA level in T regulatory cells of children with newly diagnosed type 1 diabetes.

2009 ◽  
Vol 56 (2) ◽  
Author(s):  
Włodzimierz Łuczyński ◽  
Natalia Wawrusiewicz-Kurylonek ◽  
Anna Stasiak-Barmuta ◽  
Remigiusz Urban ◽  
Elzbieta Iłendo ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
T Regulatory Cells ◽  
Mrna Level ◽  
Flow Cytometric Analysis ◽  
Treg Cells ◽  
Future Research ◽  
Mrna Levels ◽  
Newly Diagnosed ◽  
Regulatory Cells

Diabetes mellitus is one of the most common chronic diseases in children. T regulatory cells (Tregs) modulate response to autoantigens and probably play a role in pathogenesis of type 1 diabetes (T1DM). The aim of the present study was the assessment of T regulatory cells including their percentages and expression of critical genes in these cells in children with newly diagnosed type 1 diabetes. The examined group consisted of 50 children with T1DM. A flow cytometric analysis of T-cell subpopulations was performed using the following markers: anti-CD4, anti-CD25 and anti-CD127 (=IL-7R). Additionally, T regulatory cells were isolated for assessment of mRNA levels for chosen genes with the real-time RT-PCR technique. The percentages of CD4(+)CD25(high)CD127(dim/-) were very low and did not differ between T1DM and control children. We did not observe any statistically significant differences between healthy and diabetic children in mRNA expression for FoxP3, IL-7R (CD127), IL-8RA, IL-10RA, IL-12A, IL-2RA (CD25), IL-21, STAT1, STAT3, SOCS2, SOCS3, TGF-beta1-R1, TGF-beta-R2 and TBX-21 genes. Interestingly the mRNA level for CTLA-4, ICOS1, IL-23, IL-27, SMAD3 and GITR were lower in Treg cells of children with diabetes compared to the control patients. No disturbances in the percentages of T regulatory cells in patients with diabetes but diminished expression of some elements important in Treg function could be the result of an immunologic imbalance accompanying the onset of the diabetes. The results of our study should be used in future research in the field of immunotherapy in pediatric diabetes.

scholarly journals Beyond type 1 regulatory T cells: co-expression of LAG3 and CD49b in IL-10-producing T cell lineages

2018 ◽  
Author(s):  
Weishan Huang ◽  
Sabrina Solouki ◽  
Chavez Carter ◽  
Song-Guo Zheng ◽  
Avery August
Keyword(s):  
T Cells ◽  
T Cell ◽  
Treg Cells ◽  
Cell Lineages ◽  
Transgenic Murine Model ◽  
Differentiation Stage ◽  
Tr1 Cells

ABSTRACTType 1 regulatory CD4+T (Tr1) cells express high levels of the immunosuppressive cytokine IL-10 but not the master transcription factor Foxp3, and can suppress inflammation and promote immune tolerance. In order to identify and obtain viable Tr1 cells for research and clinical applications, co-expression of CD49b and LAG3 has been proposed as a unique surface signature for both human and mouse Tr1 cells. However, recent studies have revealed that this pattern of co-expression is dependent on the stimulating conditions and the differentiation stage of the CD4+T cells. Here, using an IL-10GFP/Foxp3RFPdual reporter transgenic murine model, we demonstrate that co-expression of CD49b and LAG3 is not restricted to the Foxp3−Tr1 cells, but is also observed in Foxp3+T regulatory (Treg) cells and CD8+T cells that produce IL-10. Our data indicate that IL-10-producing Tr1 cells, Treg cells and CD8+T cells are all capable of co-expressing LAG3 and CD49bin vitrofollowing differentiation under IL-10-inducing conditions, andin vivofollowing pathogenic insult or infection in the pulmonary mucosa. Our findings urge caution in the use of LAG3/CD49b co-expression to identify Tr1 cells, since it may mark IL-10-producing T cell lineages more broadly, including the Foxp3−Tr1 cells, Foxp3+Treg cells and CD8+T cells.

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