Plasmacytoid dendritic cells resident in human thymus drive natural Treg cell development

Blood ◽  
2010 ◽  
Vol 115 (26) ◽  
pp. 5366-5375 ◽  
Author(s):  
Enrique Martín-Gayo ◽  
Elena Sierra-Filardi ◽  
Angel L. Corbí ◽  
María L. Toribio
Keyword(s):  
Dendritic Cells ◽  
Transforming Growth Factor ◽  
Expression Profiles ◽  
Transforming Growth Factor Β ◽  
Cell Receptor ◽  
Cd40 Ligand ◽  
Interleukin 10 ◽  
Human Thymus ◽  
Major Subset

Abstract The generation of natural regulatory T cells (nTregs) is crucial for the establishment of immunologic self-tolerance and the prevention of autoimmunity. Still, the origin of nTregs and the mechanisms governing their differentiation within the thymus are poorly understood, particularly in humans. It was recently shown that conventional dendritic cells (cDCs) in human thymus were capable of inducing nTreg differentiation. However, the function of plasmacytoid DCs (pDCs), the other major subset of thymic DCs, remains unknown. Here we report that pDCs resident in the human thymus, when activated with CD40 ligand (CD40L) plus interleukin-3, efficiently promoted the generation of CD4+CD25+Foxp3+ nTregs from autologous thymocytes. The progenitors of these nTregs were selectively found within CD4+CD8+ thymocytes that had accomplished positive selection, as judged by their CD69hiTCRhi phenotype. Supporting the involvement of the CD40-CD40L pathway in pDC-induced nTreg generation, we show that positively selected CD4+CD8+ progenitors specifically transcribed CD40L in vivo and up-regulated CD40L expression on T-cell receptor engagement, thereby promoting the activation of pDCs. Finally, evidence is provided that nTregs primed by pDCs displayed reciprocal interleukin-10/transforming growth factor-β cytokine expression profiles compared with nTregs primed by cDCs. This functional diversity further supports a nonredundant tolerogenic role for thymic pDCs in the human thymus.

Altered T-cell receptor + CD28-mediated signaling and blocked cell cycle progression in interleukin 10 and transforming growth factor-β–treated alloreactive T cells that do not induce graft-versus-host disease

Blood ◽  
2001 ◽  
Vol 97 (2) ◽  
pp. 565-571 ◽  
Author(s):  
Vassiliki A. Boussiotis ◽  
Zong-Ming Chen ◽  
Jay C. Zeller ◽  
William J. Murphy ◽  
Alla Berezovskaya ◽  
...  
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cell Receptor ◽  
Interleukin 10 ◽  
Graft Versus Host

Abstract The induction of anergy in T cells, although widely accepted as critical for the maintenance of tolerance, is still poorly understood at the molecular level. Recent evidence demonstrates that in addition to blockade of costimulation using monoclonal antibodies (mAbs) directed against cell surface determinants, treatment of mixed lymphocyte reaction (MLR) cultures with interleukin 10 (IL-10) and transforming growth factor-β (TGF-β) results in induction of tolerance, rendering alloreactive murine CD4+ T cells incapable of inducing graft-versus-host disease (GVHD) after in vivo transfer to histoincompatible recipients. The present study, using these cells prior to adoptive transfer, determined that IL-10 + TGF-β–tolerant CD4+ T cells exhibit an altered pattern of T-cell receptor (TCR) + CD28-mediated signaling and are incapable of progressing out of the G1 phase of the cell cycle during stimulation with HLA class II disparate antigen-presenting cells. TGFβ + IL-10–tolerant cells were incapable of phosphorylating TCR-ζ, or activating ZAP-70, Ras, and MAPK, similarly to T-cell tolerized by blockade of B7/CD28 and CD40/CD40L pathways. Moreover, these cells were incapable of clonal expansion due to defective synthesis of cyclin D3 and cyclin A, and defective activation of cyclin-dependent kinase (cdk)4, cdk6, and cdk2. These cells also exhibited defective down-regulation of p27kip1 cdk inhibitor and lack of cyclin D2-cdk4 activation, Rb hyperphosphorylation, and progression to the S phase of the cell cycle. These data link anergy-specific proximal biochemical alterations and the downstream nuclear pathways that control T-cell expansion and provide a biochemical profile of IL-10 + TGF-β–tolerant alloreactive T cells that do not induce GVHD when transferred into MHC class II disparate recipients in vivo.

Human immunodeficiency virus–driven expansion of CD4+CD25+ regulatory T cells, which suppress HIV-specific CD4 T-cell responses in HIV-infected patients

Blood ◽  
2004 ◽  
Vol 104 (10) ◽  
pp. 3249-3256 ◽  
Author(s):  
Laurence Weiss ◽  
Vladimira Donkova-Petrini ◽  
Laure Caccavelli ◽  
Michèle Balbo ◽  
Cédric Carbonneil ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Highly Active Antiretroviral Therapy ◽  
Cd4 T Cells ◽  
Transforming Growth Factor ◽  
Cell Subset ◽  
Transforming Growth Factor Β ◽  
Interleukin 10

Abstract The present study demonstrates that CD4+CD25+ T cells, expanded in peripheral blood of HIV-infected patients receiving highly active antiretroviral therapy (HAART), exhibit phenotypic, molecular, and functional characteristics of regulatory T cells. The majority of peripheral CD4+CD25+ T cells from HIV-infected patients expressed a memory phenotype. They were found to constitutively express transcription factor forkhead box P3 (Foxp3) messengers. CD4+CD25+ T cells weakly proliferated to immobilized anti-CD3 monoclonal antibody (mAb) and addition of soluble anti-CD28 mAb significantly increased proliferation. In contrast to CD4+CD25– T cells, CD4+CD25+ T cells from HIV-infected patients did not proliferate in response to recall antigens and to p24 protein. The proliferative capacity of CD4 T cells to tuberculin, cytomegalovirus (CMV), and p24 significantly increased following depletion of CD4+CD25+ T cells. Furthermore, addition of increasing numbers of CD4+CD25+ T cells resulted in a dose-dependent inhibition of CD4+CD25– T-cell proliferation to tuberculin and p24. CD4+CD25+ T cells responded specifically to p24 antigen stimulation by expressing transforming growth factor β (TGF-β) and interleukin 10 (IL-10), thus indicating the presence of p24-specific CD4+ T cells among the CD4+CD25+ T-cell subset. Suppressive activity was not dependent on the secretion of TGF-β or IL-10. Taken together, our results suggest that persistence of HIV antigens might trigger the expansion of CD4+CD25+ regulatory T cells, which might induce a tolerance to HIV in vivo.

Targeting PSG1 to enhance chemotherapeutic efficacy: new application for anti-coagulant the dicumarol

2016 ◽  
Vol 130 (24) ◽  
pp. 2267-2276 ◽  
Author(s):  
Dong-xu He ◽  
Feng Gu ◽  
Jian Wu ◽  
Xiao-Ting Gu ◽  
Chun-Xiao Lu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Transforming Growth Factor ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Transforming Growth Factor Β ◽  
Clinical Samples ◽  
Breast Cancer Patients

Chemotherapeutic response is critical for the successful treatment and good prognosis in cancer patients. In this study, we analysed the gene expression profiles of preoperative samples from oestrogen receptor (ER)-negative breast cancer patients with different responses to taxane-anthracycline-based (TA-based) chemotherapy, and identified a group of genes that was predictive. Pregnancy specific beta-1-glycoprotein 1 (PSG1) played a central role within signalling pathways of these genes. Inhibiting PSG1 can effectively reduce chemoresistance via a transforming growth factor-β (TGF-β)-related pathway in ER-negative breast cancer cells. Drug screening then identified dicumarol (DCM) to target the PSG1 and inhibit chemoresistance to TA-based chemotherapy in vitro, in vivo, and in clinical samples. Taken together, this study highlights PSG1 as an important mediator of chemoresistance, whose effect could be diminished by DCM.

Activin-A: a novel dendritic cell–derived cytokine that potently attenuates CD40 ligand–specific cytokine and chemokine production

Blood ◽  
2008 ◽  
Vol 111 (5) ◽  
pp. 2733-2743 ◽  
Author(s):  
Neil C. Robson ◽  
David J. Phillips ◽  
Tristan McAlpine ◽  
Amanda Shin ◽  
Suzanne Svobodova ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Human Monocyte ◽  
Transforming Growth Factor Β ◽  
Cd40 Ligand ◽  
Activin A ◽  
Type I ◽  
Chemokine Production ◽  
Specific Effector ◽  
Factor Α

Activin-A is a transforming growth factor-β (TGF-β) superfamily member that plays a pivotal role in many developmental and reproductive processes. It is also involved in neuroprotection, apoptosis of tumor and some immune cells, wound healing, and cancer. Its role as an immune-regulating protein has not previously been described. Here we demonstrate for the first time that activin-A has potent autocrine effects on the capacity of human dendritic cells (DCs) to stimulate immune responses. Human monocyte-derived DCs (MoDCs) and the CD1c+ and CD123+ peripheral blood DC populations express both activin-A and the type I and II activin receptors. Furthermore, MoDCs and CD1c+ myeloid DCs rapidly secrete high levels of activin-A after exposure to bacteria, specific toll-like receptor (TLR) ligands, or CD40 ligand (CD40L). Blocking autocrine activin-A signaling in DCs using its antagonist, follistatin, enhanced DC cytokine (IL-6, IL-10, IL-12p70, and tumor necrosis factor-α [TNF-α]) and chemokine (IL-8, IP-10, RANTES, and MCP-1) production during CD40L stimulation, but not TLR-4 ligation. Moreover, antagonizing DC-derived activin-A resulted in significantly enhanced expansion of viral antigen-specific effector CD8+ T cells. These findings establish an immune-regulatory role for activin-A in DCs, highlighting the potential of antagonizing activin-A signaling in vivo to enhance vaccine immunogenicity.

Differentiation of Tr1 cells by immature dendritic cells requires IL-10 but not CD25+CD4+ Tr cells

Blood ◽  
2005 ◽  
Vol 105 (3) ◽  
pp. 1162-1169 ◽  
Author(s):  
Megan K. Levings ◽  
Silvia Gregori ◽  
Eleonora Tresoldi ◽  
Sabrina Cazzaniga ◽  
Chiara Bonini ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Transforming Growth Factor ◽  
Cellular Therapy ◽  
Transforming Growth Factor Β ◽  
Interleukin 10 ◽  
Peripheral Tolerance ◽  
Immature Dendritic Cells ◽  
Tr1 Cells

Abstract Dendritic cells (DCs) are specialized antigen-presenting cells that monitor the antigenic environment and activate naive T cells. The role of DCs is not only to sense danger but also to tolerize the immune system to antigens encountered in the absence of maturation/inflammatory stimuli. Indeed, if a naive T cell encounters its antigen on immature DCs (iDCs), it may differentiate into a T-regulatory (Tr) rather than a T-effector cell. However, little is known about the mechanisms by which iDCs differentiate Tr cells. We developed a standardized and highly reproducible protocol to differentiate Tr cells by repetitive exposure of naive peripheral blood CD4+ T cells to allogeneic iDCs. The resultant Tr cells are phenotypically and functionally identical to type 1 Tr (Tr1) cells because their generation requires production of IL-10 by iDCs, and they suppress T-cell responses through an interleukin-10 (IL-10)– and a transforming growth factor β (TGF-β)–dependent mechanism. In addition, Tr1 cells induced by iDCs do not require the presence of CD4+CD25+ Tr cells for their generation, nor do they express high constitutive levels of CD25 or the transcription factor FoxP3. Thus, iDCs can drive the differentiation of Tr1 cells and can be used to generate large numbers of alloantigen-specific Tr1 cells for clinical use as a cellular therapy to restore peripheral tolerance.

scholarly journals CD4+CD25+ TR Cells Suppress Innate Immune Pathology Through Cytokine-dependent Mechanisms

2003 ◽  
Vol 197 (1) ◽  
pp. 111-119 ◽  
Author(s):  
Kevin J. Maloy ◽  
Laurence Salaun ◽  
Rachel Cahill ◽  
Gordon Dougan ◽  
Nigel J. Saunders ◽  
...  
Keyword(s):  
T Cell ◽  
Transforming Growth Factor ◽  
Intestinal Inflammation ◽  
Inflammatory Diseases ◽  
Transforming Growth Factor Β ◽  
Interleukin 10 ◽  
Innate Immune ◽  
Autoimmune And Inflammatory Diseases ◽  
Immune Pathology

CD4+CD25+ regulatory T (TR) cells can inhibit a variety of autoimmune and inflammatory diseases, but the precise mechanisms by which they suppress immune responses in vivo remain unresolved. Here, we have used Helicobacter hepaticus infection of T cell–reconstituted recombination-activating gene (RAG)−/− mice as a model to study the ability of CD4+CD25+ TR cells to inhibit bacterially triggered intestinal inflammation. H. hepaticus infection elicited both T cell-mediated and T cell–independent intestinal inflammation, both of which were inhibited by adoptively transferred CD4+CD25+ TR cells. T cell–independent pathology was accompanied by activation of the innate immune system that was also inhibited by CD4+CD25+ TR cells. Suppression of innate immune pathology was dependent on T cell–derived interleukin 10 and also on the production of transforming growth factor β. Thus, CD4+CD25+ TR cells do not only suppress adaptive T cell responses, but are also able to control pathology mediated by innate immune mechanisms.

scholarly journals Efferocytosis impairs pulmonary macrophage and lung antibacterial function via PGE2/EP2 signaling

2009 ◽  
Vol 206 (1) ◽  
pp. 61-68 ◽  
Author(s):  
Alexandra I. Medeiros ◽  
Carlos H. Serezani ◽  
Sang Pyo Lee ◽  
Marc Peters-Golden
Keyword(s):  
Bacterial Infections ◽  
Transforming Growth Factor ◽  
Tissue Injury ◽  
Clinical Importance ◽  
Transforming Growth Factor Β ◽  
Interleukin 10 ◽  
Bacterial Killing ◽  
Potential Impact

The ingestion of apoptotic cells (ACs; termed “efferocytosis”) by phagocytes has been shown to trigger the release of molecules such as transforming growth factor β, interleukin-10 (IL-10), nitric oxide, and prostaglandin E2 (PGE2). Although the antiinflammatory actions of these mediators may contribute to the restoration of homeostasis after tissue injury, their potential impact on antibacterial defense is unknown. The lung is highly susceptible to diverse forms of injury, and secondary bacterial infections after injury are of enormous clinical importance. We show that ACs suppress in vitro phagocytosis and bacterial killing by alveolar macrophages and that this is mediated by a cyclooxygenase–PGE2–E prostanoid receptor 2 (EP2)–adenylyl cyclase–cyclic AMP pathway. Moreover, intrapulmonary administration of ACs demonstrated that PGE2 generated during efferocytosis and acting via EP2 accounts for subsequent impairment of lung recruitment of polymorphonuclear leukocytes and clearance of Streptococcus pneumoniae, as well as enhanced generation of IL-10 in vivo. These results suggest that in addition to their beneficial homeostatic influence, antiinflammatory programs activated by efferocytosis in the lung have the undesirable potential to dampen innate antimicrobial responses. They also identify an opportunity to reduce the incidence and severity of pneumonia in the setting of lung injury by pharmacologically targeting synthesis of PGE2 or ligation of EP2.

scholarly journals Constitutive but Not Inducible Attenuation of Transforming Growth Factor β Signaling Increases Natural Killer Cell Responses without Directly Affecting Dendritic Cells Early after Persistent Viral Infection

2015 ◽  
Vol 89 (6) ◽  
pp. 3343-3355 ◽  
Author(s):  
Gavin M. Lewis ◽  
Monica Macal ◽  
Charles R. Hesser ◽  
Elina I. Zuñiga
Keyword(s):  
Dendritic Cells ◽  
Viral Infection ◽  
Immune Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Host Responses ◽  
Chronic Viral Infection ◽  
Chronic Infections

ABSTRACTRapid innate responses to viral encounters are crucial to shaping the outcome of infection, from viral clearance to persistence. Transforming growth factor β (TGF-β) is a potent immune suppressor that is upregulated early upon viral infection and maintained during chronic infections in both mice and humans. However, the role of TGF-β signaling in regulating individual cell typesin vivois still unclear. Using infections with two different persistent viruses, murine cytomegalovirus (MCMV) and lymphocytic choriomeningitis virus (LCMV; Cl13), in their natural rodent host, we observed that TGF-β signaling on dendritic cells (DCs) did not dampen DC maturation or cytokine production in the early stages of chronic infection with either virusin vivo. In contrast, TGF-β signaling prior to (but not during) chronic viral infection directly restricted the natural killer (NK) cell number and effector function. This restriction likely compromised both the early control of and host survival upon MCMV infection but not the long-term control of LCMV infection. These data highlight the context and timing of TGF-β signaling on different innate cells that contribute to the early host response, which ultimately influences the outcome of chronic viral infectionin vivo.IMPORTANCEIn vivohost responses to pathogens are complex processes involving the cooperation of many different immune cells migrating to specific tissues over time, but these events cannot be replicatedin vitro. Viruses causing chronic infections are able to subvert this immune response and represent a human health burden. Here we used two well-characterized viruses that are able to persist in their natural mouse host to dissect the role of the suppressive molecule TGF-β in dampening host responses to infectionin vivo. This report presents information that allows an increased understanding of long-studied TGF-β signaling by examining its direct effect on different immune cells that are activated very early afterin vivoviral infection and may aid with the development of new antiviral therapeutic strategies.

Active suppression of allogeneic proliferative responses by dendritic cells after induction of long-term allograft survival by CTLA4Ig

Blood ◽  
2003 ◽  
Vol 101 (8) ◽  
pp. 3325-3333 ◽  
Author(s):  
Cécile Guillot ◽  
Séverine Ménoret ◽  
Carole Guillonneau ◽  
Cécile Braudeau ◽  
Maria G. Castro ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Combined Treatment ◽  
Interleukin 10 ◽  
No Production ◽  
Allograft Survival

Abstract Costimulatory blockade using cytotoxic T lymphocyte–associated antigen 4 immunoglobulin (CTLA4Ig) efficiently down-regulates immune responses in animal models and is currently used in autoimmune and transplantation clinical trials, but the precise cellular and molecular mechanisms involved remain unclear. Rats that received allogeneic heart transplants and were treated with adenoviruses coding for CTLA4Ig show long-term allograft survival. The immune mechanisms regulating induction of long-term allograft acceptance were analyzed in splenocytes using mixed leukocyte reactions (MLRs). MLRs of splenocytes but not purified T cells from CTLA4Ig-treated rats showed higher than 75% inhibition compared with controls. Splenocytes from CTLA4Ig-treated rats inhibited proliferation of naive and allogeneically primed splenocytes or T cells. MLR suppression was dependent on soluble secreted product(s). Production of soluble inhibitory product(s) was triggered by a donor antigen-specific stimulation and inhibited proliferation in an antigen-nonspecific manner. CTLA4Ig levels in the culture supernatant were undetectable and neither interleukin-10 (IL-10), transforming growth factor β1 (TGFβ1), IL-4, nor IL-13 were responsible for suppression of MLRs. Inhibition of nitrous oxide (NO) production or addition of IL-2 could not restore proliferation independently, but the combined treatment synergistically induced proliferation comparable with controls. Stimulation of APCs using tumor necrosis factor (TNF)–related activation-induced cytokine (TRANCE) or CD40L and addition of IL-2 normalized MLRs of CTLA4Ig-treated splenocytes. Finally, dendritic cells (DCs), but not T cells, from CTLA4Ig-treated rats inhibited naive MLRs. Altogether, these results provide evidence that after in vivo CTLA4Ig treatment, splenocytes, and in particular DCs, can inhibit alloantigen-induced proliferative responses through secretion of inhibitory products, thus promoting alloantigen-specific tolerance in vivo.

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