scholarly journals A new insight into tumor immune-evasion: Crosstalk between cancer stem cells and T regulatory cells

2020 ◽  
Author(s):  
Abhishek Dutta ◽  
Debomita Sengupta ◽  
Swastika Paul ◽  
Sourio Chakraborty ◽  
Tanya Das
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Immune System ◽  
Cancer Stem Cells ◽  
Treg Cell ◽  
Significant Role ◽  
Treg Cells ◽  
Cell Generation ◽  
Naïve T Cells

Cancer development is initiated, sustained, and aggravated by a rare population of cells, termed cancer stem cells (CSCs). Although CSCs are considered as a promising source of cells to orchestrate the immune system to work in favour of tumor, the detailed mechanisms underlying their immunomodulatory effects remain elusive. Recent reports indicate the contribution of exosomes, secreted from various cells, as mediators of cell-to-cell communication especially within the tumor microenvironment. We aimed at exploring the role of CSC-derived exosomes (CDEs) in reprogramming the host immune system by generating functional T-regulatory (Treg) cells, and at delineating the underlying mechanisms. Our results showed that CDEs play a significant role in generating CD4 + CD25 + FoxP3 + Treg cells from naive T-cells. A search for the underlying mechanism revealed the presence of FoxP3 protein in CDEs which was found to be transferred to the naïve T-cells. Exosomes from FoxP3-ablated CSCs failed to augment immuno-suppressive Treg cell generation confirming the significant role of the transported protein. In order to understand the contribution of CDE-FoxP3 in maintaining a heritably stable population of Treg cell we checked for the binding of CDE-FoxP3 on conserved non-coding sequence 2 (CNS2) region of FoxP3 promoter in T-naïve cells and found CDE-FoxP3 is indeed recruited to the CNS2 region generating stable and functionally suppressive Treg cells. These results raise the possibility that CSCs provide the initial trigger for immunosuppressive Treg cell generation and thus, breaching the deadly-liaison between them might be a promising strategy in breast cancer therapy.

scholarly journals Exosomes Secreted by Mesenchymal Stem Cells Induce Immune Tolerance to Kidney Transplantation via Transporting lncRNA DANCR

2021 ◽  
Author(s):  
Xiaoqiang Wu ◽  
Zhiwei Wang ◽  
Junpeng Wang ◽  
Xiangyong Tian ◽  
Guanghui Cao ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Kidney Transplantation ◽  
Cell Differentiation ◽  
Inflammatory Response ◽  
Treg Cell ◽  
Immune Tolerance ◽  
Treg Cells ◽  
Related Factors ◽  
T Cell Infiltration

Abstract BackgroundMesenchymal stem cells induce kidney transplant tolerance by increasing regulatory T (Treg) cells. Bone marrow mesenchymal stem cell exosomes (BMMSC-Ex) promote Treg cell differentiation. Long non-coding RNA differentiation antagonizing non-protein coding RNA (DANCR) is expressed in BMMSCs and can be encapsulated in exosomes. We aimed to explore the role of DANCR in BMMSC-Ex in immune tolerance after kidney transplantation and related mechanism.MethodsThe kidney transplantation model was established and levels of serum creatinine (SCr) were determined. Hematoxylin-eosin staining was conducted to detect the inflammation and immunohistochemistry was performed to detect the infiltration of CD4+ T cells. Levels of IFN-γ, IL-17 and IL-2 were examined by ELISA. Flow cytometry was conducted to determine Treg cells.ResultsIn allograft group, the inflammatory response was severe, CD4+ T cell infiltration, SCr levels, and plasma rejection related factors were up-regulated, while injection of BMMSC-Ex reversed the results. BMMSC-Ex increased Treg cells in kidney transplantation mice. Interference with DANCR reversed the promoting effect of BMMSC-Ex on Treg cell differentiation. DANCR bound to SIRT1, promoted ubiquitination and accelerated its degradation. The injection of BMMSC-Ex (after interference with DANCR) promoted SIRT1 levels, inflammatory response, CD4+ T cell infiltration, SCr levels, and plasma rejection related factors′ expression, while Treg cells were decreased.ConclusionLncRNA DANCR in BMMSC-Ex promoted Treg cell differentiation and induced immune tolerance of kidney transplantation by down-regulating SIRT1 expression in CD4+ T cells.

scholarly journals Cancer Stem Cells: Emerging Key Players in Immune Evasion of Cancers

2021 ◽  
Vol 9 ◽  
Author(s):  
Martina Mang Leng Lei ◽  
Terence Kin Wah Lee
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cancer Cells ◽  
Immune Cells ◽  
Immune Surveillance ◽  
Suppressor Cells ◽  
Tumor Infiltrating Lymphocytes ◽  
Treg Cells ◽  
Undifferentiated Cancer

Cancer stem cells (CSCs) are subpopulations of undifferentiated cancer cells within the tumor bulk that are responsible for tumor initiation, recurrence and therapeutic resistance. The enhanced ability of CSCs to give rise to new tumors suggests potential roles of these cells in the evasion of immune surveillance. A growing body of evidence has described the interplay between CSCs and immune cells within the tumor microenvironment (TME). Recent data have shown the pivotal role of some major immune cells in driving the expansion of CSCs, which concurrently elicit evasion of the detection and destruction of various immune cells through a number of distinct mechanisms. Here, we will discuss the role of immune cells in driving the stemness of cancer cells and provide evidence of how CSCs evade immune surveillance by exerting their effects on tumor-associated macrophages (TAMs), dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs), T-regulatory (Treg) cells, natural killer (NK) cells, and tumor-infiltrating lymphocytes (TILs). The knowledge gained from the interaction between CSCs and various immune cells will provide insight into the mechanisms by which tumors evade immune surveillance. In conclusion, CSC-targeted immunotherapy emerges as a novel immunotherapy strategy against cancer by disrupting the interaction between immune cells and CSCs in the TME.

Malignant B Cell-Derived TGF-β Controls the Generation of TH1, TH17 and Treg Cells in the Tumor Microenvironment of B-Cell Non-Hodgkin Lymphoma (NHL).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1551-1551
Author(s):  
Zhi-Zhang Yang ◽  
Anne Novak ◽  
Thomas E. Witzig ◽  
Stephen M. Ansell
Keyword(s):  
T Cells ◽  
B Cells ◽  
Tumor Microenvironment ◽  
B Cell ◽  
Cd4 T Cells ◽  
Th17 Cell ◽  
Treg Cells ◽  
Cell Generation ◽  
Human B Cell

Abstract Background: Our previous work has shown that malignant B cells induce the development of intratumoral Treg cells that inhibit the host anti-tumor response. In contrast to an increase in Treg cells, we found that the number of effector T helper cells (TH1, TH2 and TH17) was low in B-cell NHL tumors, suggesting an imbalance between Treg and TH cells in the tumor microenvironment. Understanding the mechanism(s) of this imbalance is important to the development of treatments to enhance host immunity and in previous work we have shown that signaling through CD70, CD80 and CD86 plays a role. Since soluble factors, particularly TGF-β, have an important role in directing T-cell differentiation, we evaluated in this study the role of TGF-β in the lymphoma microenvironment. Goal: To determine the effect of TGF-β on the generation of intratumoral TH1, TH17 and Treg cells in human B-cell NHL. Results: Human B-cell NHL specimens were obtained from consenting patients and were used for all experiments. Using an ELISA assay, we found that malignant B cells variably secrete TGF-β - median 100 pg/ml per million cells (range: undetectable −229 pg/ml, n=7). Using flow cytometry, we showed that addition of exogenous TGF-β enhanced the expression of Foxp3+ in activated CD4+ or CD4+CD45RA+ or CD4+CD45RO+ nodal T cells, suggesting that TGF-β promotes the generation of Treg cells in tumor microenvironment. In contrast, TGF-β suppressed expression of IFN-g in activated CD4+ T cells and inhibited the up-regulation of IL-12 and IL-23-induced IFN-γ expression in CD4+ cells, indicating that TGF-β suppresses the generation of TH1 cells. TGF-β alone slightly inhibited IL-17 expression in CD4+ T cells; however, TGF-β, in the presence of IL-6 and IL-23, upregulated IL-17 expression in CD4+ T cells, suggesting proinflammatory cytokines are able to reverse the suppression induced by TGF-β. These results indicate that TGF-β plays an important role in the regulation of intratumoral TH17 cell generation. In additional experiments, TGF-β was found to exert a suppressive effect on the proliferation of both CD4+ and CD8+ intratumoral T cells. However, treatment with TGF-β enhanced IL-2 production by intratumoral CD4+ T cells detected by intracellular staining of flow cytometry. Interruption of IL-2 signaling by anti-IL-2 Ab abolished the upregulation of TGF-β-mediated Foxp3 expression and enhanced the production of IL-17 in CD4+ T cells. Furthermore, treatment with anti-IL-2 Ab reversed the inhibition of NHL B cell-mediated TH17 cell generation. Conclusion: These results suggest that TGF-β controls the generation of TH1, TH17 and Treg cells contributing to the imbalance of effector TH cells and inhibitory Treg cells in the tumor microenvironment of B-cell NHL through IL-2. Since malignant B-cells produce TGF-β, these results further support the important role of malignant B cells in the regulation of intratumoral T cell generation and the host immune response.

CD4+CD25+ regulatory T-cell deficiency in patients with hepatitis C-mixed cryoglobulinemia vasculitis

Blood ◽  
2004 ◽  
Vol 103 (9) ◽  
pp. 3428-3430 ◽  
Author(s):  
Olivier Boyer ◽  
David Saadoun ◽  
Julien Abriol ◽  
Mélanie Dodille ◽  
Jean-Charles Piette ◽  
...  
Keyword(s):  
T Cells ◽  
Hepatitis C ◽  
Treg Cell ◽  
Mixed Cryoglobulinemia ◽  
Treg Cells ◽  
Healthy Controls ◽  
Cell Frequency ◽  
Autoantibody Production

Abstract Patients who are chronically infected with hepatitis C virus (HCV) often develop mixed cryoglobulinemia (MC), a B-cell proliferative disorder with polyclonal activation and autoantibody production. We investigated if MC is associated with a deficit of CD4+CD25+ immunoregulatory T (Treg) cells, which have been shown to control autoimmunity. Because Treg cells express higher amounts of CD25 than activated CD4+ T cells, we analyzed blood CD4+CD25high Treg cells in 69 untreated patients chronically infected with HCV. Treg cell frequency in patients without MC (8.8% ± 2.3%) or with asymptomatic MC (7.4% ± 2.1%) was comparable to that of healthy controls (7.9% ± 1.3%). In contrast, it was significantly reduced in symptomatic MC patients (2.6% ± 1.2%, P < .001) even when compared to a panel of untreated HCV- patients with different inflammatory disorders (6.2% ± 0.8%, P < .0001). In symptomatic MC patients, the purified remaining CD4+CD25+ T cells retained suppressive activity in vitro. These results, together with experimental data showing that depletion of Treg cells induces autoimmunity, suggest a major role of Treg cell deficiency in HCV-MC vasculitis and this is the first report of a quantitative Treg cell deficiency in virus-associated autoimmunity. (Blood. 2004; 103:3428-3430)

The Role of PD-1/PD-Ls in the Pathogenesis of IgG4-RD

Rheumatology ◽  
2021 ◽  
Author(s):  
Xia Zhang ◽  
Hui Lu ◽  
Linyi Peng ◽  
Jiaxin Zhou ◽  
Mu Wang ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
Submandibular Gland ◽  
Treg Cells ◽  
T Cell Subsets ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Cell Death Protein ◽  
Stimulation Of

Abstract Objective To investigate the role of Programmed cell death protein 1 (PD-1) and its two ligands PD-L1 and PD-L2 in the pathogenesis of IgG4-RD. Methods Patients with IgG4-RD (n = 43) as well as healthy controls (n = 34) were recruited. Expression levels of PD-1, PD-L1 and PD-L2 in plasma, submandibular gland and T cell subsets were determined by ELISA, immunohistochemistry and flow cytometry. Naive T cells were stimulated with or without PD-L1/PD-L2 or anti-PD-L1/anti-PD-L2 for 7 days and the proportion of CD4+CD25+Treg cells was detected by flow cytometry. Results The expression of PD-1, PD-L1 and PD-L2 in the plasma, submandibular gland and on the surface of Treg cells were increased in IgG4-RD patients. Plasma sPD-1 was positively correlated with serum IgG, IgG1, IgG3, IgG4, IgG4-RD RI and numbers of organs involved, and negatively correlated with serum IgM, IgA, C3 and C4. Plasma sPD-L2 was positively correlated with serum IgG1, plasma sPD-L1 was positively correlated with sPD-L2 and negatively correlated with C3. Stimulation of PD-L1 but not PD-L2 promoted the differentiation of naive T cells from IgG4-RD patients into CD4+CD25+Treg cells. Conclusion Plasma concentration of sPD-1, sPD-L1 and sPD-L2 were significantly increased in patients with IgG4-RD, and the expression of PD-1 and PD-L2 on Treg cells were upregulated. PD-1/PD-L1 can promote the differentiation of naive T cells into Treg cells and thus participate in the pathogenesis of IgG4-RD.

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 The Role of Forkhead Box 1 (FOXO1) in the Immune System: Dendritic Cells, T Cells, B Cells, and Hematopoietic Stem Cells

2017 ◽  
Vol 37 (1) ◽  
pp. 1-13 ◽  
Author(s):  
Adriana Alicia Cabrera-Ortega ◽  
Daniel Feinberg ◽  
Youde Liang ◽  
Carlos Rossa ◽  
Dana T. Graves
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Dendritic Cells ◽  
Immune System ◽  
B Cells ◽  
Hematopoietic Stem Cells ◽  
Hematopoietic Stem ◽  
Forkhead Box

scholarly journals IMMUNOLOGICAL MEMORY: THE ROLE OF REGULATORY CELLS (TREGS)

2018 ◽  
Vol 20 (5) ◽  
pp. 613-620
Author(s):  
E. K. Oleinik ◽  
A. V. Churov ◽  
V. M. Oleinik
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Structural Organization ◽  
Memory T Cells ◽  
Treg Cells ◽  
T Cell Memory ◽  
Peripheral Tissues

Memory T cells are necessary for development of the immune response and represent one of the most numerous population of human T lymphocytes. On the contrary, suppressive regulatory T cells (Tregs) may terminate the immune response and help to maintain tolerance to self-antigens. These important groups of cells are consisting of different subpopulations and retaining throughout life. However, today there is yet no clear understanding of how the relations between these two groups of cells are formed. In this work we consider possible ways of development and maintenance of CD4+ T cell memory and role of Tregs in these processes. Mechanisms of a differentiation of memory T cells, Tregs and recently described memory Tregs are discussed. The functional and genetic characteristics of these cells are compared. Division of cells according to the functional profile allows drawing parallels between memory T cells and Tregs. These two groups are consisted of central circulating populations (Tc), effector which can migrate toward specific tissues (Te) and tissue-resident cells (Tr), which are staying in peripheral tissues. The similar structural organization of Tregs and memory T cells, existence of transitional forms of tissue-resident Treg subpopulations with properties of memory cells assumes existence of close interrelation between these groups of lymphocytes. The conversion of CD4+ memory T cells into FoxP3-expressing Tregs is one of possible mechanisms of communication between these two groups. The memory Treg-cells with T cell and memory Treg-cell properties can represent a transitional stage of differentiation. On the other side, Treg cells can differentiate independently of memory T cells and accumulate during life in the form of memory Treg cells. The supressor function of Tregs is also necessary as well as function of memory T cells to develop the immune response. It is possible, that a subset of Treg cells undergoes selection in thymus and constitutively express TCR-receptors having affinity with peripheral tissues. Further, these committed cells can be settled into tissues and become tissue-resident Treg cells which maintain regional T cell memory. Tregs can represent the “mirror image” of the structural organization of memory T cells, but with the return sign – the sign of suppression. The quantitative ratio of Tregs and memory T cells (CD4+CD45RO+CD25hiFoxP3+/CD4+CD45RO+CD25-FoxP3-), perhaps, is important criterion for functional assessment of immune system. The balance between these functionally opposite cell subsets has to provide stable functioning of immune system.

scholarly journals The Role of Mouse Mesenchymal Stem Cells in Differentiation of Naive T-Cells into Anti-Inflammatory Regulatory T-Cell or Proinflammatory Helper T-Cell 17 Population

2012 ◽  
Vol 21 (6) ◽  
pp. 901-910 ◽  
Author(s):  
Eliska Svobodova ◽  
Magdalena Krulova ◽  
Alena Zajicova ◽  
Katerina Pokorna ◽  
Jana Prochazkova ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Mesenchymal Stem Cells ◽  
T Cell ◽  
Regulatory T Cell ◽  
Helper T Cell ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Anti Inflammatory

scholarly journals The Therapeutic Strategies of Regulatory T Cells in Malignancies and Stem Cell Transplantations

2019 ◽  
Vol 2019 ◽  
pp. 1-6 ◽  
Author(s):  
Rana G. Zaini ◽  
Amani A. Al-Rehaili
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Immune System ◽  
Regulatory T Cells ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Treg Cell ◽  
Cell Function ◽  
Treg Cells ◽  
Treg Cell Function

Regulatory T cells (Treg cells) are considered one of the main dynamic cell types within the immune system. Because Treg cells suppress immune responses, they have potential roles in immunological self-tolerance and may help to maintain immune homeostasis. Promoting Treg cell function and increasing their numbers might be useful in treating autoimmune disorders, as well as preventing allograft rejection. However, studies of mice and humans demonstrate that Treg cells promote cancer progression and suppress antitumor immunity. Therefore, suppressing Treg cell function or reducing their numbers could support the immune system’s response to pathogenic microorganisms and tumors. As a result, there is great interest in investigating the Treg cells role in the treatment of hematological and nonhematological malignancies. Consequently, Treg cells could be a fundamentally important target for pathologies of the immune system. Targeting effector Treg cells could help to distinguish and selectively decrease these cells while preserving other Treg cells needed to suppress autoimmunity. Currently, a promising way to treat malignancies and other autoimmune disorders is stem cell transplantation. Stem cell transplants (SCT) can help to manage the production of Treg cells and also may produce more efficient Treg cells, thereby suppressing clinical disease progression. Specifically, mature T cells within the engrafted stem cells mediate this SCT beneficial effect. During SCT, the recipient’s immune system is replaced with a donor, which allows for improved immune system function. In addition, SCT can protect from disease relapse, as graft-versus-host disease (GvHD) in transplant patients can be protective against cancer recurrence. The current review will define the role of regulatory T cells in treatment of malignancy. Additionally, it will summarize current promising research regarding the utility of regulatory T cells in stem cell transplantation.

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