scholarly journals TGF-β1 Drives Inflammatory Th Cell But Not Treg Cell Compartment Upon Allergen Exposure

2022 ◽  
Vol 12 ◽  
Author(s):  
Stephanie Musiol ◽  
Francesca Alessandrini ◽  
Constanze A. Jakwerth ◽  
Adam M. Chaker ◽  
Evelyn Schneider ◽  
...  
Keyword(s):  
T Cells ◽  
Therapeutic Option ◽  
Allergic Airway Inflammation ◽  
Treg Cells ◽  
Allergen Exposure ◽  
Airway Hyperreactivity ◽  
Allergen Specific Immunotherapy ◽  
Genetic Ablation ◽  
Major Player ◽  
Tgf Β1

TGF-β1 is known to have a pro-inflammatory impact by inducing Th9 and Th17 cells, while it also induces anti-inflammatory Treg cells (Tregs). In the context of allergic airway inflammation (AAI) its dual role can be of critical importance in influencing the outcome of the disease. Here we demonstrate that TGF-β is a major player in AAI by driving effector T cells, while Tregs differentiate independently. Induction of experimental AAI and airway hyperreactivity in a mouse model with inducible genetic ablation of the gene encoding for TGFβ-receptor 2 (Tgfbr2) on CD4+T cells significantly reduced the disease phenotype. Further, it blocked the induction of pro-inflammatory T cell frequencies (Th2, Th9, Th17), but increased Treg cells. To translate these findings into a human clinically relevant context, Th2, Th9 and Treg cells were quantified both locally in induced sputum and systemically in blood of allergic rhinitis and asthma patients with or without allergen-specific immunotherapy (AIT). Natural allergen exposure induced local and systemic Th2, Th9, and reduced Tregs cells, while therapeutic allergen exposure by AIT suppressed Th2 and Th9 cell frequencies along with TGF-β and IL-9 secretion. Altogether, these findings support that neutralization of TGF-β represents a viable therapeutic option in allergy and asthma, not posing the risk of immune dysregulation by impacting Tregs cells.

scholarly journals TGF-β1 drives Th9 but not Treg cells upon allergen exposure

2021 ◽  
Author(s):  
Stephanie Musiol ◽  
Francesca Alessandrini ◽  
Constanze A. Jakwerth ◽  
Adam M. Chaker ◽  
Evelyn Schneider ◽  
...  
Keyword(s):  
T Cells ◽  
Therapeutic Option ◽  
Treg Cells ◽  
Allergen Exposure ◽  
Airway Hyperreactivity ◽  
Allergen Specific Immunotherapy ◽  
Genetic Ablation ◽  
Th9 Cells ◽  
Tgf Β1 ◽  
Th9 Cell

TGF-β1 is known to have a pro-inflammatory impact by inducing Th9 cells, while it also induces anti-inflammatory Treg cells (Tregs). In the context of allergic airway inflammation (AAI) its dual role can be of critical importance in influencing the outcome of the disease. Here we demonstrate that TGF-β acts in AAI by driving effector T cells into Th9 cells, while Tregs differentiate independently. Induction of experimental AAI and airway hyperreactivity in a mouse model with inducible genetic ablation of the TGFβ-receptor 2 (TGFBR2) on CD4+T cells significantly reduced the disease phenotype. Further, it blocked the induction of Th9 cell frequencies, but increased Treg cells. To translate these findings into a human clinically relevant context, Th9 and Treg cells were quantified both locally in induced sputum and systemically in blood of allergic rhinitis and asthma patients with or without allergen-specific immunotherapy (AIT). Natural allergen exposure induced local and systemic Th2, Th9 cell and reduced Tregs, while therapeutic allergen exposure by AIT suppressed Th2 and Th9 cell frequencies along with TGF-β and IL-9 secretion. Altogether, these findings support that neutralization of TGF-β represents a viable therapeutic option in allergy and asthma, not posing the risk of immune dysregulation by impacting Tregs.

scholarly journals Impact of immune checkpoint molecules on FoxP3+ Treg cells and related cytokines in patients with acute and chronic brucellosis

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Hua-Li Sun ◽  
Xiu-Fang Du ◽  
Yun-Xia Tang ◽  
Guo-Qiang Li ◽  
Si-Yuan Yang ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Checkpoint ◽  
Treg Cells ◽  
Shanxi Province ◽  
Healthy Controls ◽  
Chronic Patients ◽  
Immune Checkpoint Molecules ◽  
Significant Difference ◽  
Acute Patients ◽  
Tgf Β1

Abstract Background The immunoregulatory functions of regulatory T cells (Tregs) in the development and progression of some chronic infectious diseases are mediated by immune checkpoint molecules and immunosuppressive cytokines. However, little is known about the immunosuppressive functions of Tregs in human brucellosis, which is a major burden in low-income countries. In this study, expressions of immune checkpoint molecules and Treg-related cytokines in patients with acute and chronic Brucella infection were evaluated to explore their impact at different stages of infection. Methods Forty patients with acute brucellosis and 19 patients with chronic brucellosis admitted to the Third People’s Hospital of Linfen in Shanxi Province between August 2016 and November 2017 were enrolled. Serum and peripheral blood mononuclear cells were isolated from patients before antibiotic treatment and from 30 healthy subjects. The frequency of Tregs (CD4+ CD25+ FoxP3+ T cells) and expression of CTLA-4, GITR, and PD-1 on Treg cells were detected by flow cytometry. Levels of Treg-related cytokines, including IL-35, TGF-β1, and IL-10, were measured by customised multiplex cytokine assays using the Luminex platform. Results The frequency of Tregs was higher in chronic patients than in healthy controls (P = 0.026) and acute patients (P = 0.042); The frequency of CTLA-4+ Tregs in chronic patients was significantly higher than that in healthy controls (P = 0.011). The frequencies of GITR+ and PD-1+ Tregs were significantly higher in acute and chronic patients than in healthy controls (P < 0.05), with no significant difference between the acute and chronic groups (all P > 0.05). Serum TGF-β1 levels were higher in chronic patients (P = 0.029) and serum IL-10 levels were higher in acute patients (P = 0.033) than in healthy controls. We detected weak correlations between serum TGF-β1 levels and the frequencies of Tregs (R = 0.309, P = 0.031) and CTLA-4+ Tregs (R = 0.302, P = 0.035). Conclusions Treg cell immunity is involved in the chronicity of Brucella infection and indicates the implication of Tregs in the prognosis of brucellosis. CTLA-4 and TGF-β1 may contribute to Tregs-mediated immunosuppression in the chronic infection stage of a Brucella infection.

Influences of High-Dose Dexamethasone on Regulatory T Cells, Transforming Growth Factor-β1 and Interleukin-10 of Patients with Chronic ITP.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3920-3920
Author(s):  
Yun Ling ◽  
Xiangshan Cao ◽  
Ziqiang Yu ◽  
Changgeng Ruan
Keyword(s):  
T Cells ◽  
Transforming Growth Factor ◽  
Interleukin 10 ◽  
Treg Cells ◽  
Transforming Growth Factor Β1 ◽  
High Dose ◽  
Chronic Itp ◽  
High Dose Dexamethasone ◽  
Significant Difference ◽  
Tgf Β1

Abstract Immune thrombocytopenic purpura (ITP) is an autoimmune disorder and high-dose dexamethasone (HD-DXM) has been used as a first-line therapy for patients with ITP. However, little is known about the role of CD4+CD25 + regulatory T (Treg) cells, interleukin-10 (IL-10) and transforming growth factor-β1 (TGF-β1) in the pathogenesis of chronic ITP and the effects of HD-DXM on them contained Treg cells, IL-10 and TGF-β1. In this study, we investigated the expressions of Treg cells, IL-10 and TGF-β1 in 26 untreated adult patients with chronic ITP. All patients had thrombocytopenia (platelet count &lt;50 × 109/L) for more than 6 months. We also observed short time changes of Treg cells, IL-10 and TGF-β1 after treatment with HD-DXM in these patients. The results showed that a good initial response to HD-DXM occurred in 24 of the 26 patients with chronic ITP (92.3%): the mean platelet count was (84.9±30.4)×109/L [range, (20∼150) ×109/L] one week after the initiation of treatment. The proportion of CD4+CD25+ T cells in the peripheral blood of patients with chronic ITP was significantly higher than that in normal controls(P&lt;0.001); there was no significant difference in the percentage of CD4+CD25high T cells between patients and controls ( P=0.317); but the number of CD4+ FOXP3+ T cells in patients was significantly lower than that in controls (P&lt;0.001). After 4-days treatment with HD-DXM, the numbers of CD4+ CD25+ T cells (P&lt;0.001), CD4+CD25high T cells ( P&lt;0.001), and CD4+FOXP3+ T cells ( P&lt;0.001) in patients were all significantly increased. In the serum of chronic ITP patients, the expression level of TGF-β1 was lower than that of healthy controls (P&lt;0.0001) and HD-DXM could significantly increase it; there was no significant difference in the expression level of IL-10 between patients and controls ( P&gt;0.05) and there was no remarkable change of IL-10 in patients after HD-DXM treatment (P&gt;0.05). The mRNA levels of Foxp3 and TGF-β1 gene in patients were lower than those of controls (P&lt;0.05 and P&lt;0.05); HD-DXM administration significantly increased the expressions of Foxp3 and TGF-β1 gene(P&lt;0.05 and P&lt;0.0001), which were even higher than those of controls(P&lt;0.05 and P&lt;0.05); There was a positive correlation between the Foxp3 mRNA expression and TGF-β1 after treatment with HD-DXM (r =0.403, P=0.041). These results suggest that Foxp3 and TGF-β1 gene are deficient in chronic ITP and the immunosuppressive therapy of glucocorticoids could improve the expression levels of these genes.

High Efficiency Isolation of Alloantigen-Reactive Foxp3+ Natural Regulatory T Cells According to Specific Activation Marker Signatures

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1915-1915
Author(s):  
Anne Schoenbrunn ◽  
Jacqueline Keye ◽  
Siegfried Kohler ◽  
Marco Frentsch ◽  
Beate Moewes ◽  
...  
Keyword(s):  
T Cells ◽  
High Efficiency ◽  
Tumor Antigens ◽  
Therapeutic Option ◽  
Adoptive Cell Therapy ◽  
Tolerance Induction ◽  
Treg Cells ◽  
Immunosuppressive Drugs ◽  
Transplant Tolerance

Abstract Abstract 1915 Transplant tolerance induction and avoidance of exposure to destructive immunosuppressive drugs are still major objectives in transplantation medicine. Many preclinical animal models have proven the adoptive transfer of polyclonal CD4+CD25+Foxp3+ regulatory T (Treg) cells to be an important and effective tool for the prevention of graft rejection or graft-versus-host-disease. However, polyclonal Treg may also modulate immunity to foreign or tumor antigens. It is unclear yet, whether and how their application might lead to an unwanted general immunosuppression. Therefore the selective transfer of alloantigen-reactive Treg represents a very attractive therapeutic option. However, so far this strategy has been hampered so far by the lack of appropriate marker to assess and isolate antigen-reactive Treg cells with high efficiency. In order to get access to alloantigen-reactive Treg, we established cytometric methodologies allowing a clear dissection between (allo)antigen-specific Treg and Teff based on expression of 4-1BB and the lack of expression of CD40L. After allogeneic stimulation CD4+ T cells expressing 4-1BB but lacking CD40L expression were highly enriched in Foxp3+ T cells. Further molecular analysis of the Foxp3 gene locus revealed that only 4-1BB+CD40L− T cells were characterised by a completely demethylated TSDR (Treg specific demethylated region). 4-1BB+CD40L− T cells highly expressed the transcription factor HELIOS recently demonstrated to specify thymic-derived Treg. Alloantigen-reactive Treg isolated according to 4-1BB and CD40L were superior with respect to their alloantigen-specific in vitro suppression as compared their polyclonal Treg counterparts. Finally 4-1BB+CD40L− alloantigen-reactive Treg could be easily expanded in vitro up to 300 fold during 3 weeks culture, maintaining alloantigen-specific suppression. Our results offer the possibility to improve current approaches for adoptive cell-therapy with alloantigen-specific Treg to achieve transplantation tolerance aiming at a specific inhibition of pathology. Disclosures: Scheffold: Miltenyi Biotec GmbH: Employment.

scholarly journals Modulating Shrimp Tropomyosin-Mediated Allergy: Hypoallergen DNA Vaccines Induce Regulatory T Cells to Reduce Hypersensitivity in Mouse Model

2019 ◽  
Vol 20 (18) ◽  
pp. 4656 ◽  
Author(s):  
Christine Y.Y. Wai ◽  
Nicki Y.H. Leung ◽  
Patrick S.C. Leung ◽  
Ka Hou Chu
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Dna Vaccines ◽  
Specific Ige ◽  
Treg Cells ◽  
Food Allergies ◽  
Allergen Specific Immunotherapy ◽  
Intradermal Administration ◽  
And Migration ◽  
Shellfish Allergy

Shellfish allergy is one of the most common food allergies, with tropomyosin as the major cross-reactive allergen. However, no allergen-specific immunotherapy is clinically available. Recently, we designed two shrimp hypoallergens MEM49 and MED171. This study aimed to examine and compare the efficacy of the MEM49- and MED171-based DNA vaccines (pMEM49 and pMED171) in modulating shrimp allergy in a murine model of shrimp tropomyosin sensitivity. Intradermal immunization of BALB/c mice with pMEM49 or pMED171 effectively down-modulated allergic symptoms, tropomyosin-specific IgE levels, intestinal Th2 cytokines expression, and inflammatory cell infiltration. Both pMEM49 and pMED171 increased the frequency of regulatory T cells, but to a greater extent by pMED171 with upregulation of gut-homing molecules integrin-α4β7. The functionality of the pMED171-induced Treg cells was further illustrated by anti-CD25-mediated depletion of Treg cells and the adoptive transfer of CD4+CD25+Foxp3+Treg cells. Collectively, the data demonstrate that intradermal administration of pMED171 leads to the priming, activation, and migration of dermal dendritic cells which subsequently induce Treg cells, both locally and systemically, to downregulate the allergic responses to tropomyosin. This study is the first to demonstrate the potency of hypoallergen-encoding DNA vaccines as a therapeutic strategy for human shellfish allergy via the vigorous induction of functional Treg cells.

A Dendritic Cells-Targeting Nano-Vaccine by Coupling Polylactic-Co-Glycolic Acid-Encapsulated Allergen with Mannan Induces Regulatory T Cells

2021 ◽  
pp. 1-11
Author(s):  
He Wen ◽  
Litian Qu ◽  
Yu Zhang ◽  
Beilei Xu ◽  
Shiqi Ling ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Glycolic Acid ◽  
Tolerance Induction ◽  
Treg Cells ◽  
Intercellular Adhesion Molecule ◽  
Allergen Specific Immunotherapy ◽  
Th2 Immune Response

<b><i>Background:</i></b> The efficacy of allergen-specific immunotherapy (AIT) is mainly depended on the tolerogenic immune responses elicited. Properly conjugated nano-vaccine has the advantages of both specific targeting and continuous and on-demand release of allergen. <b><i>Objectives:</i></b> The aim of this study is to investigate the effects of a dendritic cells (DCs)-targeting nano-vaccine for AIT. <b><i>Methods:</i></b> The nano-vaccine was produced by coupling polylactic-co-glycolic acid (PLGA)-encapsulated ovalbumin (OVA) with mannan. Allergen capture, human monocytes-derived DCs (hMoDCs) activation, and T cells responses were assessed by flow cytometry, confocal microscopy, quantitative real-time PCR, ELISA, and Cytometric Bead Array. Balb/c mice were immunized with the nano-vaccines, and the immune responses were analyzed. <b><i>Results:</i></b> OVA-PLGA nanoparticle (NP) displayed favorable safety profile. OVA-mannan-PLGA NP was captured more efficiently by hMoDCs than OVA-PLGA NP, which was mediated mainly through DC-specific intercellular adhesion molecule 3-grabbing nonintegrin. A tolerogenic phenotype of hMoDCs was induced by OVA-mannan-PLGA NP, but not OVA-PLGA NP, and increased number of regulatory T (Treg) cells was generated subsequently in in vitro coculture. Immunization of Balb/c mice with OVA-mannan-PLGA NP resulted in lower serum level of OVA-specific immunoglobulins and less production of pro-inflammatory cytokines in splenocytes culture than the mice immunized with OVA-PLAG NP, PLGA NP, or OVA, while the number of splenic Treg cells was higher in OVA-mannan-PLGA group than in other groups. Moreover, preimmunization with OVA-mannan-PLGA NP significantly inhibited the Th2 immune response induced by OVA sensitization. <b><i>Conclusions:</i></b> The biocompatible PLGA-encapsulated OVA coupling with mannan has augmented ability for tolerance induction and could be developed as a novel vaccine for AIT.

scholarly journals Critical Roles of Balanced T Helper 9 Cells and Regulatory T Cells in Allergic Airway Inflammation and Tumor Immunity

2021 ◽  
Vol 2021 ◽  
pp. 1-20
Author(s):  
Muhua Huang ◽  
Jingcheng Dong
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Airway Inflammation ◽  
Tumor Immunity ◽  
Allergic Airway Inflammation ◽  
Treg Cells ◽  
T Helper ◽  
Th Cells ◽  
Th9 Cells ◽  
And Function

CD4+T helper (Th) cells are important mediators of immune responses in asthma and cancer. When counteracted by different classes of pathogens, naïve CD4+T cells undergo programmed differentiation into distinct types of Th cells. Th cells orchestrate antigen-specific immune responses upon their clonal T-cell receptor (TCR) interaction with the appropriate peptide antigen presented on MHC class II molecules expressed by antigen-presenting cells (APCs). T helper 9 (Th9) cells and regulatory T (Treg) cells and their corresponding cytokines have critical roles in tumor and allergic immunity. In the context of asthma and cancer, the dynamic internal microenvironment, along with chronic inflammatory stimuli, influences development, differentiation, and function of Th9 cells and Treg cells. Furthermore, the dysregulation of the balance between Th9 cells and Treg cells might trigger aberrant immune responses, resulting in development and exacerbation of asthma and cancer. In this review, the development, differentiation, and function of Th9 cells and Treg cells, which are synergistically regulated by various factors including cytokine signals, transcriptional factors (TFs), costimulatory signals, microenvironment cues, metabolic pathways, and different signal pathways, will be discussed. In addition, we focus on the recent progress that has helped to achieve a better understanding of the roles of Th9 cells and Treg cells in allergic airway inflammation and tumor immunity. We also discuss how various factors moderate their responses in asthma and cancer. Finally, we summarize the recent findings regarding potential mechanisms for regulating the balance between Th9 and Treg cells in asthma and cancer. These advances provide opportunities for novel therapeutic strategies that are aimed at reestablishing the balance of these cells in the diseases.

scholarly journals Ectopic FOXP3 Expression in Combination with TGF-β1 and IL-2 Stimulation Generates Limited Suppressive Function in Human Primary Activated Thymocytes Ex Vivo

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 461
Author(s):  
Jorge Gallego-Valle ◽  
Sergio Gil-Manso ◽  
Ana Pita ◽  
Esther Bernaldo-de-Quirós ◽  
Rocío López-Esteban ◽  
...  
Keyword(s):  
T Cells ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Interleukin 2 ◽  
Foxp3 Expression ◽  
Treg Cells ◽  
Cytokine Signaling ◽  
Suppressive Function ◽  
Tgf Β1

Regulatory T cells (Tregs), which are characterized by the expression of the transcription factor forkhead box P3 (FOXP3), are the main immune cells that induce tolerance and are regulators of immune homeostasis. Natural Treg cells (nTregs), described as CD4+CD25+FOXP3+, are generated in the thymus via activation and cytokine signaling. Transforming growth factor beta type 1 (TGF-β1) is pivotal to the generation of the nTreg lineage, its maintenance in the thymus, and to generating induced Treg cells (iTregs) in the periphery or in vitro arising from conventional T cells (Tconvs). Here, we tested whether TGF-β1 treatment, associated with interleukin-2 (IL-2) and CD3/CD28 stimulation, could generate functional Treg-like cells from human thymocytes in vitro, as it does from Tconvs. Additionally, we genetically manipulated the cells for ectopic FOXP3 expression, along with the TGF-β1 treatment. We demonstrated that TGF-β1 and ectopic FOXP3, combined with IL-2 and through CD3/CD28 activation, transformed human thymocytes into cells that expressed high levels of Treg-associated markers. However, these cells also presented a lack of homogeneous suppressive function and an unstable proinflammatory cytokine profile. Therefore, thymocyte-derived cells, activated with the same stimuli as Tconvs, were not an appropriate alternative for inducing cells with a Treg-like phenotype and function.

scholarly journals Induction of Immune Tolerance in Asthmatic Mice by Vaccination with DNA Encoding an Allergen–Cytotoxic T Lymphocyte-Associated Antigen 4 Combination

2011 ◽  
Vol 18 (5) ◽  
pp. 807-814 ◽  
Author(s):  
Fang Zhang ◽  
Gang Huang ◽  
Bo Hu ◽  
Yong Song ◽  
Yi Shi
Keyword(s):  
Airway Inflammation ◽  
Dna Vaccine ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Treg Cells ◽  
Airway Hyperreactivity ◽  
Interleukin 4 ◽  
High Dose ◽  
Dna Encoding ◽  
Allergen Specific Immunotherapy

ABSTRACTAllergen-specific immunotherapy is a potential treatment for allergic diseases. We constructed an allergen–cytotoxic T lymphocyte-associated antigen 4 (CTLA-4)-encoding DNA vaccine, administered it directly to antigen-presenting cells (APCs), and investigated its ability and mechanisms to ameliorate allergic airway inflammation in an asthmatic mouse model. An allergen-CTLA-4 DNA plasmid (OVA-CTLA-4-pcDNA3.1) encoding an ovalbumin (OVA) and the mouse CTLA-4 extracellular domain was constructed and transfected into COS-7 cells to obtain the fusion protein OVA-CTLA-4, which was able to bind the B7 ligand on dendritic cells (DCs), and induced CD25+Foxp3+regulatory T (Treg) cells by the coculture of naive CD4+T cells with DCsin vitro. In an animal study, BALB/c mice were sensitized and challenged with OVA to establish the asthmatic model. Vaccination with a high dose of OVA-CTLA-4-pcDNA3.1significantly decreased interleukin-4 (IL-4) and IL-5 levels and eosinophil counts and prevented OVA-induced reduction of the gamma interferon level in the bronchoalveolar lavage fluid. In addition, these mice suffered less severe airway inflammation and had lower levels of OVA-specific IgE and IgG1 titers in serum. Also, high-dose OVA-CTLA-4-pcDNA3.1vaccination inhibited the development of airway hyperreactivity and prevented OVA-induced reduction of the percentages of Foxp3+Treg cells in the spleen. Our results indicate that a high dose of allergen-CTLA-4-encoding DNA vaccine was more effective in preventing an allergen-induced Th2-skewed immune response through the induction of Treg cells and may be a new alternative therapy for asthma.

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