scholarly journals Assessment of Allergen-Responsive Regulatory T Cells in Experimental Asthma Induced in Different Mouse Strains

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
C. T. Azevedo ◽  
A. C. Cotias ◽  
A. C. S. Arantes ◽  
T. P. T. Ferreira ◽  
M. A. Martins ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Allergic Asthma ◽  
Treg Cell ◽  
Allergen Challenge ◽  
Treg Cells ◽  
Airway Hyperreactivity ◽  
Whole Body ◽  
Mouse Strains ◽  
Th2 Response

Background. Regulatory T cells (Tregs) are important in regulating responses to innocuous antigens, such as allergens, by controlling the Th2 response, a mechanism that appears to be compromised in atopic asthmatic individuals. Different isogenic mouse strains also have distinct immunological responses and susceptibility to the experimental protocols used to develop lung allergic inflammation. In this work, we investigated the differences in the frequency of Treg cell subtypes among A/J, BALB/c, and C57BL/6, under normal conditions and following induction of allergic asthma with ovalbumin (OVA). Methods. Subcutaneous sensitization followed by 4 consecutive intranasal OVA challenges induced asthma characteristic changes such as airway hyperreactivity, inflammation, and production of Th2 cytokines (IL-4, IL-13, IL-5, and IL-33) in the lungs of only A/J and BALB/c but not C57BL/6 strain and evaluated by invasive whole-body plethysmography, flow cytometry, and ELISA, respectively. Results. A/J strain naturally showed a higher frequency of CD4+IL-10+ T cells in the lungs of naïve mice compared to the other strains, accompanied by higher frequencies of CD4+IL-4+ T cells. C57BL/6 mice did not develop lung inflammation and presented higher frequency of CD4+CD25+Foxp3+ Treg cells in the bronchoalveolar lavage fluid (BALF) after the allergen challenge. In in vitro settings, allergen-specific stimulation of mediastinal LN (mLN) cells from OVA-challenged animals induced higher frequency of CD4+IL-10+ Treg cells from A/J strain and CD4+CD25+Foxp3+ from C57BL/6. Conclusions. The observed differences in the frequencies of Treg cell subtypes associated with the susceptibility of the animals to experimental asthma suggest that CD4+CD25+Foxp3+ and IL-10-producing CD4+ Treg cells may play different roles in asthma control. Similar to asthmatic individuals, the lack of an efficient regulatory response and susceptibility to the development of experimental asthma in A/J mice further suggests that this strain could be preferably chosen in experimental models of allergic asthma.

scholarly journals Cytotoxic-T-Lymphocyte-Associated Antigen 4 Blockade Abrogates Protection by Regulatory T Cells in a Mouse Model of Microbially Induced Innate Immune-Driven Colitis

2008 ◽  
Vol 76 (12) ◽  
pp. 5834-5842 ◽  
Author(s):  
Koichiro Watanabe ◽  
Varada P. Rao ◽  
Theofilos Poutahidis ◽  
Barry H. Rickman ◽  
Masahiro Ohtani ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Treg Cell ◽  
T Lymphocyte ◽  
Bacterial Infections ◽  
Cytotoxic T Lymphocyte ◽  
Interleukin 2 ◽  
Treg Cells ◽  
Innate Immune ◽  
Cell Transfer

ABSTRACT Cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) expressed at high levels by CD4+ CD25+ CD45RBlow regulatory T cells (Treg) is essential to their homeostatic and immunoregulatory functions. However, its relevance to anti-inflammatory roles of Treg in the context of colitogenic innate immune response during pathogenic bacterial infections has not been examined. We showed earlier in Rag2-deficient 129/SvEv mice that Treg cells are capable of suppressing colitis and colon cancer triggered by Helicobacter hepaticus, a widespread murine enterohepatic pathogen. Using this model, we now examined the effects of antibody blockade of CTLA-4 on Treg function during innate immune inflammatory response. Consistent with our previous findings, we found that a single adoptive transfer of Treg cells prior to infection prevented colitis development despite persistent H. hepaticus infection in recipient mice. However, when infected mice were injected with anti-CTLA-4 antibody along with Treg cell transfer, they developed a severe acute colitis with poor body condition that was not observed in Rag2−/− mice without Treg cell transfer. Despite high numbers of Foxp3+ Treg cells, evident by immunohistochemical analyses in situ, the CTLA-4 antibody-treated mice had severely inflamed colonic mucosa and increased rather than decreased expression levels of cytokines gamma interferon and interleukin-2. These findings indicate that antibody blockade of CTLA-4 clearly abrogates Treg cell ability to suppress innate immune-driven colitis and suggest that Treg cell CTLA-4 cognate interactions may be necessary to maintain homeostasis among cells of innate immunity.

R404 – Regulatory T Cells and Clinical Outcome in HNSCC Patients

2008 ◽  
Vol 139 (2_suppl) ◽  
pp. P178-P178
Author(s):  
Osama Alhamarneh ◽  
Nicholas D. Stafford ◽  
John Greenman
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Clinical Outcome ◽  
Treg Cell ◽  
Cell Population ◽  
Peripheral Blood ◽  
Treg Cells ◽  
Clinicopathological Parameters ◽  
Pre Treatment ◽  
Disease Stages

Problem To determine the correlation between peripheral blood CD4+CD25high regulatory T cells (Treg), a suppressor cell population that dampen the immune response, and clinical outcome and survival in HNSCC patients. Methods Treg cell numbers in the peripheral blood of newly-presenting, untreated HNSCC patients (n=65) were determined pre-operatively, 4–6 weeks after treatment (n=30) and in a cohort of healthy controls (n=35) of similar age and sex, after Treg cell isolation using magnetic microbeads (Miltenyi Biotec) by flow cytometry. The Mann-Whitney U test was used to analyse the correlations between Treg cell levels and clinical outcome. Results Treg cells were significantly higher in patients pre-operatively vs. controls (p=0.002). After treatment, patients showed a significant rise compared with their pre-treatment levels (p=0.022). Pre-treatment Treg cells levels did not correlate with survival or any of the other conventional clinicopathological parameters. However, higher Treg cells levels were discovered in the advanced disease stages (III/IV vs. I/II, median 6.3 vs 4.3) in the pre-treatment group that turned into significantly higher levels in the early disease stages post treatment (I/II vs. III/IV, median 10.8 vs. 5.67 p=0.044). Conclusion Although peripheral blood Treg cells levels were higher in patients when compared to controls, no correlation was found between this cell population and clinical outcome or survival. In contrast with gastric, colorectal and ovarian tumors, Treg cell levels did not normalize 4–6 weeks after curative treatment in this cohort of HNSCC patients. Studies into Treg cell function are thus required to try and elucidate the apparent paradox in Treg cell levels observed in HNSCC. Significance The presence of Regulatory T cells in the peripheral blood of HNSCC patients may be detrimental to host defence against tumor. Further studies are needed to explore their role in the tumor microenvironment and their correlation with clinical outcome.

scholarly journals The relationship between human thymus-derived regulatory T cells, TGF-β-induced regulatory T cells and conventional CD4+ T cells as revealed by proteomics

2021 ◽  
Author(s):  
Mark Mensink ◽  
Ellen Schrama ◽  
Maartje van den Biggelaar ◽  
Derk Amsen ◽  
Jannie Borst ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Protein Expression ◽  
Treg Cell ◽  
Ex Vivo ◽  
Foxp3 Expression ◽  
Treg Cells ◽  
Cell Populations ◽  
The Relationship

The CD4+ regulatory T (Treg) cell lineage, as defined by FOXP3 expression, comprises thymus-derived (t)Treg cells and peripherally induced (p)Treg cells. In human, naive tTreg cells can be purified from blood, but occur in low abundance, while effector pTreg and tTreg cell populations cannot be purified for lack of discriminating cell surface markers. Therefore, studies often employ TGF-β-induced (i)Treg cells that are generated from CD4+ conventional T (Tconv) cells in vitro. Here, we describe the relationship of iTreg cells to tTreg and Tconv cells, as optimally purified from human blood. Global proteomic analysis revealed that iTreg, tTreg and Tconv cell populations each have a unique protein expression pattern. We next used as a benchmark a previously defined proteomic signature that discerns ex vivo naive and effector phenotype Treg cells from Tconv cells and reflects unique Treg cell properties. This Treg cell core signature was largely absent from iTreg cells, while clearly present in simultaneously analyzed tTreg cells. In addition, we used a proteomic signature that distinguishes ex vivo effector Treg cells from Tconv cells and naive Treg cells. This effector Treg cell signature was partially present in iTreg cells. Thus, iTreg cells are distinct from tTreg cells and largely lack the common Treg cell proteomic signature. However, they do have certain protein expression features in common with ex vivo effector Treg cells. These data demonstrate the utility of the core and effector Treg cell signatures as tools to define Treg cell populations and encourage the use of ex vivo Treg cells for functional analyses.

scholarly journals A DAP5/eIF3d alternate mRNA translation mechanism promotes differentiation and immune suppression by human regulatory T cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Viviana Volta ◽  
Sandra Pérez-Baos ◽  
Columba de la Parra ◽  
Olga Katsara ◽  
Amanda Ernlund ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
Regulatory T Cells ◽  
Treg Cell ◽  
Immune Suppression ◽  
Mrna Translation ◽  
Treg Cells ◽  
Cell Maturation ◽  
Tgf Beta ◽  
Translation Mechanism

AbstractRegulatory T cells (Treg cells) inhibit effector T cells and maintain immune system homeostasis. Treg cell maturation in peripheral sites requires inhibition of protein kinase mTORC1 and TGF-beta-1 (TGF-beta). While Treg cell maturation requires protein synthesis, mTORC1 inhibition downregulates it, leaving unanswered how Treg cells achieve essential mRNA translation for development and immune suppression activity. Using human CD4+ T cells differentiated in culture and genome-wide transcription and translation profiling, here we report that TGF-beta transcriptionally reprograms naive T cells to express Treg cell differentiation and immune suppression mRNAs, while mTORC1 inhibition impairs translation of T cell mRNAs but not those induced by TGF-beta. Rather than canonical mTORC1/eIF4E/eIF4G translation, Treg cell mRNAs utilize the eIF4G homolog DAP5 and initiation factor eIF3d in a non-canonical translation mechanism that requires cap-dependent binding by eIF3d directed by Treg cell mRNA 5’ noncoding regions. Silencing DAP5 in isolated human naive CD4+ T cells impairs their differentiation into Treg cells. Treg cell differentiation is mediated by mTORC1 downregulation and TGF-beta transcriptional reprogramming that establishes a DAP5/eIF3d-selective mechanism of mRNA translation.

scholarly journals Resolution of airway inflammation and hyperreactivity after in vivo transfer of CD4+CD25+ regulatory T cells is interleukin 10 dependent

2005 ◽  
Vol 202 (11) ◽  
pp. 1539-1547 ◽  
Author(s):  
Jennifer Kearley ◽  
Jane E. Barker ◽  
Douglas S. Robinson ◽  
Clare M. Lloyd
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Airway Inflammation ◽  
Intracellular Cytokine Staining ◽  
Allergen Challenge ◽  
Interleukin 10 ◽  
Airway Hyperreactivity ◽  
Th2 Cytokine ◽  
Th2 Cell

Deficient suppression of T cell responses to allergen by CD4+CD25+ regulatory T cells has been observed in patients with allergic disease. Our current experiments used a mouse model of airway inflammation to examine the suppressive activity of allergen-specific CD4+CD25+ T cells in vivo. Transfer of ovalbumin (OVA) peptide–specific CD4+CD25+ T cells to OVA-sensitized mice reduced airway hyperreactivity (AHR), recruitment of eosinophils, and T helper type 2 (Th2) cytokine expression in the lung after allergen challenge. This suppression was dependent on interleukin (IL) 10 because increased lung expression of IL-10 was detected after transfer of CD4+CD25+ T cells, and regulation was reversed by anti–IL-10R antibody. However, suppression of AHR, airway inflammation, and increased expression of IL-10 were still observed when CD4+CD25+ T cells from IL-10 gene–deficient mice were transferred. Intracellular cytokine staining confirmed that transfer of CD4+CD25+ T cells induced IL-10 expression in recipient CD4+ T cells, but no increase in IL-10 expression was detected in airway macrophages, dendritic cells, or B cells. These data suggest that CD4+CD25+ T cells can suppress the Th2 cell–driven response to allergen in vivo by an IL-10–dependent mechanism but that IL-10 production by the regulatory T cells themselves is not required for such suppression.

Role of regulatory T-cells in autoimmunity

2009 ◽  
Vol 116 (8) ◽  
pp. 639-649 ◽  
Author(s):  
Richard J. Mellanby ◽  
David C. Thomas ◽  
Jonathan Lamb
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Treg Cell ◽  
Cell Function ◽  
Cell Subset ◽  
Treg Cells ◽  
Self Tolerance

There has been considerable historical interest in the concept of a specialist T-cell subset which suppresses over-zealous or inappropriate T-cell responses. However, it was not until the discovery that CD4+CD25+ T-cells had suppressive capabilities both in vitro and in vivo that this concept regained credibility and developed into one of the most active research areas in immunology today. The notion that in healthy individuals there is a subset of Treg-cells (regulatory T-cells) involved in ‘policing’ the immune system has led to the intensive exploration of the role of this subset in disease resulting in a number of studies concluding that a quantitative or qualitative decline in Treg-cells is an important part of the breakdown in self-tolerance leading to the development of autoimmune diseases. Although Treg-cells have subsequently been widely postulated to represent a potential immunotherapy option for patients with autoimmune disease, several studies of autoimmune disorders have demonstrated high numbers of Treg-cells in inflamed tissue. The present review highlights the need to consider a range of other factors which may be impairing Treg-cell function when considering the mechanisms involved in the breakdown of self-tolerance rather than focussing on intrinsic Treg-cell factors.

scholarly journals Transcriptional Control of Regulatory T Cells in Cancer: Toward Therapeutic Targeting?

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3194
Author(s):  
Pierre Stéphan ◽  
Raphaëlle Lautraite ◽  
Allison Voisin ◽  
Yenkel Grinberg-Bleyer
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Treg Cell ◽  
Transcriptional Control ◽  
Molecular Mechanisms ◽  
Treg Cells ◽  
Multiple Strategies ◽  
Cell Transcriptome ◽  
And Function ◽  
Novel Therapeutic

Extensive research in the past decades has highlighted the tight link between immunity and cancer, leading to the development of immunotherapies that have revolutionized cancer care. However, only a fraction of patients display durable responses to these treatments, and a deeper understanding of the cellular and mechanisms orchestrating immune responses to tumors is mandatory for the discovery of novel therapeutic targets. Among the most scrutinized immune cells, Forkhead Box Protein P3 (Foxp3)+ Regulatory T cells (Treg cells) are central inhibitors of protective anti-tumor immunity. These tumor-promoting functions render Treg cells attractive immunotherapy targets, and multiple strategies are being developed to inhibit their recruitment, survival, and function in the tumor microenvironment. In this context, it is critical to decipher the complex and multi-layered molecular mechanisms that shape and stabilize the Treg cell transcriptome. Here, we provide a global view of the transcription factors, and their upstream signaling pathways, involved in the programming of Treg cell homeostasis and functions in cancer. We also evaluate the feasibility and safety of novel therapeutic approaches aiming at targeting specific transcriptional regulators.

scholarly journals Intestinal Regulatory T Cells as Specialized Tissue-Restricted Immune Cells in Intestinal Immune Homeostasis and Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Justin Jacobse ◽  
Jing Li ◽  
Edmond H. H. M. Rings ◽  
Janneke N. Samsom ◽  
Jeremy A. Goettel
Keyword(s):  
Inflammatory Bowel Disease ◽  
T Cells ◽  
Regulatory T Cells ◽  
Treg Cell ◽  
Bowel Disease ◽  
Cell Biology ◽  
Intestinal Inflammation ◽  
Treg Cells ◽  
Food Antigens ◽  
Inflammatory Bowel

FOXP3+ regulatory T cells (Treg cells) are a specialized population of CD4+ T cells that restrict immune activation and are essential to prevent systemic autoimmunity. In the intestine, the major function of Treg cells is to regulate inflammation as shown by a wide array of mechanistic studies in mice. While Treg cells originating from the thymus can home to the intestine, the majority of Treg cells residing in the intestine are induced from FOXP3neg conventional CD4+ T cells to elicit tolerogenic responses to microbiota and food antigens. This process largely takes place in the gut draining lymph nodes via interaction with antigen-presenting cells that convert circulating naïve T cells into Treg cells. Notably, dysregulation of Treg cells leads to a number of chronic inflammatory disorders, including inflammatory bowel disease. Thus, understanding intestinal Treg cell biology in settings of inflammation and homeostasis has the potential to improve therapeutic options for patients with inflammatory bowel disease. Here, the induction, maintenance, trafficking, and function of intestinal Treg cells is reviewed in the context of intestinal inflammation and inflammatory bowel disease. In this review we propose intestinal Treg cells do not compose fixed Treg cell subsets, but rather (like T helper cells), are plastic and can adopt different programs depending on microenvironmental cues.

scholarly journals Interleukin-33-Dependent Accumulation of Regulatory T Cells Mediates Pulmonary Epithelial Regeneration During Acute Respiratory Distress Syndrome

2021 ◽  
Vol 12 ◽  
Author(s):  
Wen Tan ◽  
Bohan Zhang ◽  
Xinpei Liu ◽  
Chaoji Zhang ◽  
Jianzhou Liu ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Respiratory Distress Syndrome ◽  
Regulatory T Cells ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Treg Cell ◽  
Distress Syndrome ◽  
Treg Cells ◽  
Epithelial Regeneration ◽  
Tgf Β1

Acute respiratory distress syndrome (ARDS) triggered mostly by infection, is a syndrome that involves respiratory failure. ARDS induces strong local infiltration of regulatory T cells (Treg cells) in the lungs, and Treg cells were recently highlighted as being related to the repair of various tissue. However, at present, there is still a lack of adequate evidence showing the impact of Treg cells on pulmonary regeneration during ARDS. Here, we verified that Treg cells are strongly induced in ARDS mice and Treg depletion results in impaired lung repair. Moreover, Treg cells show high expression of ST2, a cellular receptor for the tissue alarmin IL-33, which is strongly upregulated in the lung during ARDS. In addition, we demonstrated that IL-33 signaling is crucial for Treg cell accumulation, and ST2-blocked mice show a decrease in the Treg cell population. Critically, transfer of exogenous IL-33 into Treg depleted mice restored Treg cells and facilitated lung regeneration by promoting alveolar type II cell (AEC2) recovery in ARDS, with elevated neutrophils infiltration and upregulated TGF-β1 release. These results emphasized the importance of IL-33 in accelerating the expansion of pulmonary Treg cells and promoting their activity to mediate pulmonary epithelial regeneration during ARDS in a TGF-β1-dependent manner.

Therapeutic Effect of CXCR3-Expressing Regulatory T Cells on Liver and Intestinal Damages in a Murine Acute GVHD Model.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2161-2161
Author(s):  
Jun Yamanouchi ◽  
Hitoshi Hasegawa ◽  
Atsushi Inoue ◽  
Masashi Kohno ◽  
Hiroshi Fujiwara ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Treg Cell ◽  
Chemokine Receptor ◽  
Acute Gvhd ◽  
Organ Damage ◽  
Treg Cells ◽  
Therapeutic Effects ◽  
Target Organs ◽  
Significant Difference

Abstract [Purpose] Adoptive transfer of CD4+CD25+ regulatory T cells has been shown to have therapeutic effects in experimental graft-versus-host disease (GVHD) models. Chemokines play an important role in the recruitment of alloreactive donor T cells into target organs during GVHD. In this study, we investigated the effectiveness of targeted delivery of CD4+CD25+ regulatory T cells via a transfected chemokine receptor on reduction of organ damage during acute GVHD. [Materials & Methods] Haploidentical parent-to-F1 transplants were performed, in which lethally irradiated B6D2F1 mice were given T cell-depleted BM cells supplemented with splenic T cells from C57BL/6. Expression of Th1-associated chemokines (CXCL9, CXCL10, and CXCL11) and their receptor CXCR3 in target organs during acute GVHD was examined with real-time PCR and ELISA assay. CD4+CD25+Foxp3+ T cells (Treg cells) were reprogrammed by infection of recombinant retrovirus carrying Foxp3 gene into cultured CD4+CD25+ T cells of donor C57BL/6 mice. CD4+CD25+Foxp3+ CXCR3-transfected T cells (CXCR3-Treg cells) were isolated by FACS sorting after infection with recombinant retrovirus carrying CXCR3 into Treg cells. Treg and CXCR3-Treg cells were transferred 7 days after BMT and histopathological analysis was preformed 35 days after BMT. The infiltration of Treg and CXCR3-Treg cells into target organs was analyzed with Foxp3 expression and fluorescence. [Results] High levels of expression of Th1-associated chemokines and their receptor CXCR3 were observed in the liver and intestines of GVHD-induced recipient mice from 1 to 3 weeks post-BMT. There was no significant difference in suppressive properties between Treg and CXCR3-Treg cells. However, in the CXCL10-driven chemotactic assay, the chemotactic activity of CXCR3-Treg cells was much higher (>100-fold) than that of Treg cells. Either 4 × 105 or 1 × 106 cells were injected into the mice 1 week after BMT, and the mice were then monitored in terms of clinical GVHD score, before being sacrified four weeks after the injection of regulatory T cells for evaluation of the pathological changes. Recipient mice that had undergone transfer of 1 × 106 CXCR3-Treg cells demonstrated a significantly reduced (P<0.01) clinical GVHD score and weight loss compared with Treg cell-transferred recipients (at 4 weeks after injection: clinical GVHD score, 0.25 ± 0.5 vs 5.25 ± 0.5; and weight change, 104.4% ± 1.9% vs 87.2% ± 4.7%, respectively). The recipients that had undergone transfer of 1 × 106 CXCR3-Treg cells showed a significantly reduced (P<0.05) histopathological GVHD score for the liver and intestines compared with Treg cell-transferred recipients (liver, 1.36 ± 0.38 vs 7.71 ± 1.07; and intestines, 1.00 vs 5.00 ± 1.35, respectively). The localization of CXCR3-Treg cells to the liver and intestines was increased significantly at 24 h and 7 days after transfer compared with that of Treg cells, and the regional localization continued to increase until 28 days post-BMT. These findings indicate that, in comparison with Treg cells, more CXCR3-Treg cells migrate into CXCL10-expressing target organs, and remain localized there for a longer time, resulting in stronger suppressive activity. [Conclusion] We succeeded in preparing chemokine receptor-expressing Treg cells and demonstrated their ability to ameliorate disease progression upon accumulation in target organs. This method may provide a new therapeutic approach for organ damage in acute GVHD.

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