Regulatory T cells in cancer

Blood ◽  
2006 ◽  
Vol 108 (3) ◽  
pp. 804-811 ◽  
Author(s):  
Marc Beyer ◽  
Joachim L. Schultze
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Characteristic Feature ◽  
Cell Biology ◽  
Foxp3 Expression ◽  
Hematologic Malignancies ◽  
Treg Cells ◽  
Effector T Cells ◽  
Murine Models ◽  
Cellular Mechanisms

Abstract Increasing evidence supports the existence of elevated numbers of regulatory T cells (Treg cells) in solid tumors and hematologic malignancies. Whereas the biology of CD4+CD25+FOXP3+ Treg cells in murine models seems to be rather straightforward, studies in human diseases are more difficult to interpret due to expression of CD25 on activated effector T cells as well as Treg cells. More importantly, early studies in human tumors were mainly focused on CD4+CD25+ Treg cells lacking interrogation of more specific markers such as FOXP3 expression. Although the increase of Treg cells seems to be a characteristic feature in most tumors, little is known about the molecular and cellular mechanisms responsible for the increase and maintenance of elevated levels of Treg cells in cancer. We will discuss earlier data in the context of recent findings in Treg-cell biology with a particular emphasis on CD4+CD25highFOXP3+ Treg cells in human malignancies.

scholarly journals Secretome screening reveals immunomodulating functions of IFNα-7, PAP and GDF-7 on regulatory T-cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mei Ding ◽  
Rajneesh Malhotra ◽  
Tomas Ottosson ◽  
Magnus Lundqvist ◽  
Aman Mebrahtu ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Cell Function ◽  
Foxp3 Expression ◽  
Treg Cells ◽  
Secreted Proteins ◽  
External Stimulation ◽  
Marker Proteins ◽  
Positive Regulators ◽  
Conformational Model

AbstractRegulatory T cells (Tregs) are the key cells regulating peripheral autoreactive T lymphocytes. Tregs exert their function by suppressing effector T cells. Tregs have been shown to play essential roles in the control of a variety of physiological and pathological immune responses. However, Tregs are unstable and can lose the expression of FOXP3 and suppressive functions as a consequence of outer stimuli. Available literature suggests that secreted proteins regulate Treg functional states, such as differentiation, proliferation and suppressive function. Identification of secreted proteins that affect Treg cell function are highly interesting for both therapeutic and diagnostic purposes in either hyperactive or immunosuppressed populations. Here, we report a phenotypic screening of a human secretome library in human Treg cells utilising a high throughput flow cytometry technology. Screening a library of 575 secreted proteins allowed us to identify proteins stabilising or destabilising the Treg phenotype as suggested by changes in expression of Treg marker proteins FOXP3 and/or CTLA4. Four proteins including GDF-7, IL-10, PAP and IFNα-7 were identified as positive regulators that increased FOXP3 and/or CTLA4 expression. PAP is a phosphatase. A catalytic-dead version of the protein did not induce an increase in FOXP3 expression. Ten interferon proteins were identified as negative regulators that reduced the expression of both CTLA4 and FOXP3, without affecting cell viability. A transcriptomics analysis supported the differential effect on Tregs of IFNα-7 versus other IFNα proteins, indicating differences in JAK/STAT signaling. A conformational model experiment confirmed a tenfold reduction in IFNAR-mediated ISG transcription for IFNα-7 compared to IFNα-10. This further strengthened the theory of a shift in downstream messaging upon external stimulation. As a summary, we have identified four positive regulators of FOXP3 and/or CTLA4 expression. Further exploration of these Treg modulators and their method of action has the potential to aid the discovery of novel therapies for both autoimmune and infectious diseases as well as for cancer.

scholarly journals CD38 Correlates with an Immunosuppressive Treg Phenotype in Lupus-Prone Mice

2021 ◽  
Vol 22 (21) ◽  
pp. 11977
Author(s):  
Jocelyn C. Pérez-Lara ◽  
Enrique Espinosa ◽  
Leopoldo Santos-Argumedo ◽  
Héctor Romero-Ramírez ◽  
Gabriela López-Herrera ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Immune Activation ◽  
Lupus Erythematosus ◽  
Clinical Signs ◽  
Foxp3 Expression ◽  
Cell Receptor ◽  
Treg Cells ◽  
Transmembrane Glycoprotein ◽  
Ifn Γ

CD38 is a transmembrane glycoprotein expressed by T-cells. It has been reported that patients with systemic lupus erythematosus (SLE) showed increased CD38+CD25+ T-cells correlating with immune activation and clinical signs. Contrariwise, CD38 deficiency in murine models has shown enhanced autoimmunity development. Recent studies have suggested that CD38+ regulatory T-cells are more suppressive than CD38− regulatory T-cells. Thus, we have suggested that CD38 overexpression in SLE patients could play a role in regulating immune activation cells instead of enhancing it. This study found a correlation between CD38 with FoxP3 expression and immunosuppressive molecules (CD69, IL-10, CTLA-4, and PD-1) in T-cells from lupus-prone mice (B6.MRL-Faslpr/J). Additionally, B6.MRL-Faslpr/J mice showed a decreased proportion of CD38+ Treg cells regarding wild-type mice (WT). Furthermore, Regulatory T-Cells (Treg cells) from CD38-/- mice showed impairment in expressing immunosuppressive molecules and proliferation after stimulation through the T-cell receptor (TCR). Finally, we demonstrated an increased ratio of IFN-γ/IL-10 secretion in CD38-/- splenocytes stimulated with anti-CD3 compared with the WT. Altogether, our data suggest that CD38 represents an element in maintaining activated and proliferative Treg cells. Consequently, CD38 could have a crucial role in immune tolerance, preventing SLE development through Treg cells.

scholarly journals The TLR9 Agonist Cobitolimod Induces IL10-Producing Wound Healing Macrophages and Regulatory T Cells in Ulcerative Colitis

2019 ◽  
Vol 14 (4) ◽  
pp. 508-524 ◽  
Author(s):  
Heike Schmitt ◽  
Julia Ulmschneider ◽  
Ulrike Billmeier ◽  
Michael Vieth ◽  
Patrizio Scarozza ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Wound Healing ◽  
T Cells ◽  
Regulatory T Cells ◽  
Th17 Cells ◽  
Experimental Colitis ◽  
Foxp3 Expression ◽  
Treg Cells ◽  
Tlr9 Agonist ◽  
Anti Inflammatory

Abstract Background and Aims The topically applied Toll-like receptor 9 [TLR9] agonist cobitolimod is a first-in-class DNA-based oligonucleotide with demonstrated therapeutic efficacy in clinical trials with ulcerative colitis [UC] patients. We here characterized its anti-inflammatory mechanism in UC. Methods Luminal cobitolimod administration was evaluated in an experimental dextran sodium sulfate [DSS]-induced colitis model. Cultured blood and mucosal cells from UC patients were treated with cobitolimod and analysed via microarray, quantitative real-time PCR, ELISA and flow cytometry. Intestinal slides of cobitolimod-treated UC patients were analysed by immunohistochemistry. Results Cobitolimod administration markedly suppressed experimental colitis activity, and microarray analyses demonstrated mucosal IL10 upregulation and suppression of IL17 signalling pathways. Cobitolimod treatment was associated with significant induction of mucosal IL10+Tr1 and Treg cells and suppression of Th17 cells. TLR9 knockout mice indicated that cobitolimod requires TLR9 signalling for IL10 induction. In UC patients, mucosal TLR9 levels correlated with severity of inflammation. Cobitolimod inhibited IL17A and IL17F, but increased IL10 and FoxP3 expression in cultured intestinal UC T cells. Cobitolimod-mediated suppression of intestinal IL17+T cells was abrogated by IL10 blockade. Furthermore, cobitolimod led to heightened IL10 production by wound healing macrophages. Immunohistochemistry in intestinal biopsies of cobitolimod-treated UC patients indicated increased presence of IL10+mononuclear and regulatory T cells, as well as reduction of IL17+cells. Conclusion Activation of TLR9 via cobitolimod might represent a novel therapeutic approach in UC, as it suppresses Th17 cells and induces anti-inflammatory IL10+macrophages and regulatory T cells, thereby modifying the dysregulated intestinal cytokine balance. Podcast This article has an associated podcast which can be accessed at https://academic.oup.com/ecco-jcc/pages/podcast

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 Immunomodulatory Effects of Rhinovirus and Enterovirus Infections During the First Year of Life

2021 ◽  
Vol 11 ◽  
Author(s):  
Terhi Ruohtula ◽  
Anita Kondrashova ◽  
Jussi Lehtonen ◽  
Sami Oikarinen ◽  
Anu-Maaria Hämäläinen ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Viral Infections ◽  
Foxp3 Expression ◽  
Treg Cells ◽  
Birth Cohort Study ◽  
Temporal Association ◽  
Immunomodulatory Effects ◽  
One Year ◽  
Th1 And Th2 Responses

Early childhood infections have been implicated in the development of immune-mediated diseases, such as allergies, asthma, and type 1 diabetes. We set out to investigate the immunomodulatory effects of early viral infections experienced before the age of one year on the peripheral regulatory T cell population (Treg) and circulating cytokines in a birth-cohort study of Estonian and Finnish infants. We show here a temporal association of virus infection with the expression of FOXP3 in regulatory T cells. Infants with rhinovirus infection during the preceding 30 days had a higher FOXP3 expression in Treg cells and decreased levels of several cytokines related to Th1 and Th2 responses in comparison to the children without infections. In contrast, FOXP3 expression was significantly decreased in highly activated (CD4+CD127−/loCD25+FOXP3high) regulatory T cells (TregFOXP3high) in the infants who had enterovirus infection during the preceding 30 or 60 days. After enterovirus infections, the cytokine profile showed an upregulation of Th1- and Th17-related cytokines and a decreased activation of CCL22, which is a chemokine derived from dendritic cells and associated with Th2 deviation. Our results reveal that immunoregulatory mechanisms are up-regulated after rhinovirus infections, while enterovirus infections are associated with activation of proinflammatory pathways and decreased immune regulation.

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.

Induction of Mouse Naive T Cells Transition into CD4+ CD2+ FoxP3+ Regulatory T Cells in a Modified Culture Medium As a Potential Armament in Graft-Versus-Host Disease

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5426-5426
Author(s):  
Tzeon-Jye Chiou ◽  
Tan-Hwa Chu ◽  
Sin-Tak Chu ◽  
Woan-Fang Tzeng
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Foxp3 Expression ◽  
Treg Cells ◽  
Activated T Cells ◽  
Allogeneic Hsct

Abstract Allogeneic hematopoietic stem cell transplantation (HSCT) has been used to treat some of hematological malignancies and inherited or acquired non-malignant disorders. Unfortunately, graft-versus-host disease (GVHD) occurred approximately 15% in transplant recipients and impacts on the outcome of allogeneic HSCT. At present, no effective modality could completely prevent the GVHD from allogeneic HSCT patients. CD4+ CD25+ FoxP3+ regulatory T cells (Tregs) have been shown to be important in maintaining immune homeostasis and preventing autoimmunity. However, 5% to 10% Tregs could be measured in human CD4+ T cells and few Tregs would convert to conventional activated T cells because of losing FoxP3 expression orn Tregs in suppression of T cell activation. It had been reported to correlate with the occurrence and severity of GVHD in some study. In order to study the potential use of CD4+ CD25+ FoxP3+ Tregs for the prevention of GVHD, we attempt to evaluate the better efficient method to increase the number of induced Treg cells (i Tregs) in donor and stabilize the FoxP3 ini Treg cells. Using mouse as a model, the splenocytes were prepared from mouse spleen. Before having biological function,i Treg cells need to stabilize the FoxP3 protein expression. Using retinoic acid (RA, 0.1-5ng/ml) as a stabilizer of the FoxP3 protein expression can keep thei Treg cells in stable. The endogenous regulatory T cells (n Treg) can inhibit T cell activation, thereby affecting T cells intoi Treg efficiency. We should remove the n Treg cells from the CD4+ T cells. Therefore, CD4+ T cells were isolated by negative selection, and then using the n Treg removing kit, we harvested the CD4+ CD62L+ naïve T cells fori Treg cell induction. For this purpose, naïve CD4+ cells were harvested, and then activated with anti-CD3/CD28 Dynabeads in the presence of IL-2, TGF-β1 and retinoic acid (RA) containing RPMI1640 medium. During the Tregs induction, the activated T cells were performed under low nutrient supplement (5% FBS) for three days then refreshed the cells into the full nutrient supplement (10% FBS) for another four days. The harvested cells were analyzed by flow cytometry method with fluorescence-conjugated CD-antibodies, including CD4, CD25, CD127, CD62L and FoxP3. Currently, the removal of n Treg cells could improve the efficiency of i Treg cell formation from 15% to 70-80% under this modified culture method (Fig.1). Further improvement of human peripheral blood regulatory T cell generation efficiency is our ongoing target. Our study showed that the combination of IL-2, TGF-β1 and RA in 3-day-nutrient-deprived medium could convert naïve CD4+ CD62L+ T cells to CD4+ CD25+ FoxP3+i Treg cells and stabilize FoxP3 expression in thei Treg cells efficiently. Further, we will develop thei Treg suppression assay to clarify the biological function ofi Tregs in vitro. GVHD mouse model will be established by using allogeneic HSCT to verify the function of i Tregs in vivo, too. Disclosures No relevant conflicts of interest to declare.

scholarly journals G Protein-Coupled Receptor 83 Is Dispensable for the Development and Function of Regulatory T Cells

2007 ◽  
Vol 27 (23) ◽  
pp. 8065-8072 ◽  
Author(s):  
Li-Fan Lu ◽  
Marc A. Gavin ◽  
Jeffrey P. Rasmussen ◽  
Alexander Y. Rudensky
Keyword(s):  
T Cells ◽  
G Protein ◽  
Treg Cell ◽  
Cell Biology ◽  
Molecular Mechanisms ◽  
Foxp3 Expression ◽  
Treg Cells ◽  
G Protein Coupled Receptor ◽  
And Function ◽  
G Protein Coupled

ABSTRACT Global analyses of gene expression in regulatory T (Treg) cells, whose development is critically dependent upon the transcription factor Foxp3, have provided many clues as to the molecular mechanisms these cells employ to control immune responses and establish immune tolerance. Through these studies, G protein-coupled receptor 83 (GPR83) was found to be expressed at high levels in Treg-cell populations. However, its function remained unclear. Recently, it has been suggested that GPR83 is involved in the induction of Foxp3 expression in the peripheral nonregulatory Foxp3− CD4 T cells. To examine a role for GPR83 in Treg-cell biology, we generated and characterized GPR83-deficient mice. We have shown that GPR83 abolition does not result in measurable pathology or changes in the numbers or function of Foxp3+ Treg cells. Furthermore, while in vitro analysis suggested a potential involvement of GPR83 in transforming growth factor β-dependent Foxp3 induction, there was no difference in the ability of nonregulatory GPR83-deficient and nondeficient Foxp3− T cells to acquire Foxp3 expression in vivo. Collectively, our results demonstrate that GPR83 is dispensable for Treg-cell development and function.

scholarly journals ROLE OF THE REGULATORY T CELLS IN PROGRESSION OF PROSTATE CANCER

2019 ◽  
Vol 21 (4) ◽  
pp. 587-594
Author(s):  
S. V. Popov ◽  
N. V. Sturov ◽  
N. V. Vorobyev ◽  
S. V. Khaidukov
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
Regulatory T Cells ◽  
Prostate Gland ◽  
Foxp3 Expression ◽  
Treg Cells ◽  
Cancer Tissue ◽  
Clinical Prognosis ◽  
Treg Population ◽  
T Cell Subpopulations

The existing data on regulatory T cells (Tregs) in prostate cancer suggest that these cells may penetrate the prostate gland malignant tissue, suppressing antitumor immune response, thus promoting aggressive clinical course and low survival of the cancer patients. Evaluation of T cell subpopulations from the tumor microenvironment has shown that the number of CD4+Tregs is associated with inferior clinical prognosis. In particular, each additional CD4+Treg cell has been shown to cause a statistically significant increase in prostate cancer mortality by 12%, regardless of other clinical factors. There are several possible explanations for the increased infiltration of prostate cancer tissue with regulatory T cells. Firstly, malignant cells or tumor-associated macrophages are capable of secreting chemokine CCL22, which has an affinity for the CCR4 receptor expressed on Treg cells. Secondly, cytokines secreted by prostate tumors, such as TGF-β, may regulate the FoxP3 expression, thus expanding the Treg population. TGF-β, in turn, is a multifunctional cytokine that promotes survival and proliferation of transformed cells, including prostate epithelium, as evidenced by increased amounts in the patients with metastatic disease.

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