scholarly journals CCR7 is required for the in vivo function of CD4+ CD25+ regulatory T cells

2007 ◽  
Vol 204 (4) ◽  
pp. 735-745 ◽  
Author(s):  
Martin A. Schneider ◽  
Josef G. Meingassner ◽  
Martin Lipp ◽  
Henrietta D. Moore ◽  
Antal Rot
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
Wild Type ◽  
Immunodeficient Mice ◽  
Cognate Antigen ◽  
Inflammatory Bowel ◽  
Secondary Lymphoid Organs

CCR7-mediated migration of naive T cells into the secondary lymphoid organs is a prerequisite for their encounter with mature dendritic cells, the productive presentation of cognate antigen, and consequent T cell proliferation and effector differentiation. Therefore, CCR7 was suggested to play an important role in the initiation of adaptive immune responses. In this study, we show that primary immunity can also develop in the absence of CCR7. Moreover, CCR7-deficient knockout (KO) mice display augmented immune responses. Our data cumulatively suggest that enhanced immunity in CCR7 KO mice is caused by the defective lymph node (LN) positioning of FoxP3+ CD4+ CD25+ regulatory T cells (T reg cells) and the consequent impediment of their function. The FoxP3+ T reg cells express CCR7 and, after their adoptive transfer, migrate into the LNs of wild-type mice. Here, they proliferate in situ upon antigen stimulation and inhibit the generation of antigen-specific T cells. Conversely, transferred CCR7-deficient T reg cells fail to migrate into the LNs and suppress antigen-induced T cell responses. The transfer of combinations of naive and T reg cells from wild-type and CCR7 KO mice into syngeneic severe combined immunodeficient mice directly demonstrates that CCR7-deficient T reg cells are less effective than their wild-type counterparts in preventing the development of inflammatory bowel disease.

scholarly journals New differentiation pathway for double-negative regulatory T cells that regulates the magnitude of immune responses

Blood ◽  
2006 ◽  
Vol 109 (9) ◽  
pp. 4071-4079 ◽  
Author(s):  
Dong Zhang ◽  
Wei Yang ◽  
Nicolas Degauque ◽  
Yan Tian ◽  
Allison Mikita ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cell Surface ◽  
Immune Responses ◽  
Lymphoid Tissues ◽  
Double Negative ◽  
Healthy Humans

Abstract Recent studies have demonstrated that in peripheral lymphoid tissues of normal mice and healthy humans, 1% to 5% of αβ T-cell receptor–positive (TCR+) T cells are CD4−CD8− (double-negative [DN]) T cells, capable of down-regulating immune responses. However, the origin and developmental pathway of DN T cells is still not clear. In this study, by monitoring CD4 expression during T-cell proliferation and differentiation, we identified a new differentiation pathway for the conversion of CD4+ T cells to DN regulatory T cells. We showed that the converted DN T cells retained a stable phenotype after restimulation and that furthermore, the disappearance of cell-surface CD4 molecules on converted DN T cells was a result of CD4 gene silencing. The converted DN T cells were resistant to activation-induced cell death (AICD) and expressed a unique set of cell-surface markers and gene profiles. These cells were highly potent in suppressing alloimmune responses both in vitro and in vivo in an antigen-specific manner. Perforin was highly expressed by the converted DN regulatory T cells and played a role in DN T-cell–mediated suppression. Our findings thus identify a new differentiation pathway for DN regulatory T cells and uncover a new intrinsic homeostatic mechanism that regulates the magnitude of immune responses. This pathway provides a novel, cell-based, therapeutic approach for preventing allograft rejection.

scholarly journals FVIII-Specific TCR Engineered Human Regulatory T Cells Suppress the Production of FVIII-Specific Responses Vitro and In Vivo

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2586-2586
Author(s):  
Yong Chan Kim ◽  
Aihong Zhang ◽  
Jeong-Heon Yoon ◽  
David W. Scott
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
Hemophilia A ◽  
Cell Receptor ◽  
Cell Contact ◽  
Therapeutic Trial

Abstract Expanded antigen-specific engineered regulatory T cells (Tregs) have been proposed for potential clinical application for the treatment of undesirable immune responses, such as inhibitor responses in hemophilia A patients and autoimmune diseases. By providing an antigen-specific T-cell receptor (TCR) to polyclonal natural Tregs, we suggested that antigen-specific engineered Tregs would migrate specifically to particular target tissues and induce antigen-specific immune tolerance in the local milieu. Previously, we developed FVIII C2-specific Tregs using a long-term stabilization protocol in vitro and demonstrated that these stabilized engineered Tregs successfully modulated FVIII-specific T-cell and B-cell immune responses in vitro. Furthermore, these engineered Tregs could suppress T-effectors specific for additional epitopes in local milieu in both a cell contact and contactless manner. From these data, we hypothesized that IL-2 and related signaling pathways are major regulatory mechanisms of the suppression. To further investigate how IL-2R signaling is engaged to control T effectors and Tregs, we followed the phospho-STAT5 status of these cells kinetically. Our results showed clearly that IL-2 from activated T effectors is a key requirement for Treg activation, inducing subsequent blockage of STAT5 signal in T effectors by activated Tregs. As further evidence of the efficacy of these specific Tregs, we then determined whether FVIII C2-specific Tregs could suppress the induction of FVIII inhibitor antibody in vivo. Thus, we transferred FVIII C2-specific human Tregs into HLA DR1 hemophilic mice and challenged them with FVIII in vivo. Our results showed that induction of FVIII-specific antibodies was inhibited for over 8 weeks. Taken together, our results suggest a potential therapeutic trial of FVIII-specific engineered Tregs in hemophilia A. Disclosures Kim: Henry Jackson Foundation: Patents & Royalties: Provisional submitted.

Critical Role of Neutrophils in Determining Antigen-Specific CD4+ T-Cell Tolerance In Vivo.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3294-3294
Author(s):  
Fengdong Cheng ◽  
Pedro Horna ◽  
Hongwei Wang ◽  
Ildefonso Suarez ◽  
Xianhong Chen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
High Dose ◽  
Wild Type ◽  
Cognate Antigen ◽  
Induced Tolerance

Abstract In previous studies we have shown that Signal Transducer and Activator of Transcription 3 (STAT3) negatively regulates inflammatory responses in myeloid cells and plays a central role in determining immune activation versus immune tolerance of antigen-specific CD4+ T-cells. Indeed, in Stat3 knock out mice (LysMcre/Stat3flox/−) in which macrophages and neutrophils are devoid of Stat3, we found that in response to a tolerogenic stimulus (high dose peptide-induced tolerance or tumor-induced tolerance models) adoptively transferred antigen-specific CD4+ T-cells are not tolerized but instead are effectively primed as determined by their production of IL-2 and IFN-gamma in response to cognate antigen. Such an observation led us to investigate which cell population(s) is required for the priming effect observed in Stat3 KO mice. First, we used anti-Gr-1 antibody to deplete neutrophils in wild type BALB/c mice as well as Stat3 KO mice. Briefly, half the mice in each group were treated with 0.5mg of the antibody given i.p. every 3 days from day-3 until day +15. On day zero, all the mice were adoptively transferred with 2.5 x 106 naïve transgenic CD4+ T-cells specific for a MHC class II restricted epitope of hemaglutinin (HA). On day +2, animals received high dose of HA peptide (275 mcg) given i.v. Mice were sacrificed on day +15 and clonotypic T-cells were re-isolated from their spleens to assess their functional status following their in vivo exposure to this tolerogenic stimuli. A striking difference was observed in T-cells isolated from Stat3 KO mice with an intact neutrophil compartment (non-depleted) versus T-cells from anti-Gr-1 treated LysMcreStat3flox/− mice. Unlike T-cells from the former group in which priming was the functional outcome, clonotypic T-cells from LysMcreStat3flox/− mice depleted of neutrophils, were found to be anergic. Therefore, the T-cell priming effect observed in LysMcreStat3flox/− mice requires an intact neutrophil compartment given that in the absence of this population, tolerance not priming was the functional T-cell outcome. To gain insight into the potential mechanism(s) by which neutrophils devoid of Stat3 influence T-cell responses, we next analyzed the phenotypic and functional properties of neutrophils isolated from Stat3 KO mice and wild type controls. First, the lack of expression of MHC class II molecules by neutrophils from WT and KO mice made unlikely the possibility that neutrophils devoid of Stat3 could directly present antigen to CD4+ T-cells. However, when neutrophils from Stat3−/− conditional mice were added to macrophages monolayers in vitro, the antigen-presenting capabilities of macrophages was significantly enhanced as determined by the increased production of IL-2 and IFN-gamma by antigen-specific T-cells encountering cognate antigen in these APCs. Furthermore, macrophages cultured in vitro with neutrophils from Stat3−/− conditional mice were able to restore the responsiveness of tolerant CD4+ T-cells. This effect that was not observed when tolerized T-cells encountered cognate antigen in macrophages incubated with neutrophils from wild type mice. Trans-well experiments demonstrated that the regulatory effect of neutrophils upon APCs function required cell-cell contact. Taken together, we have unveiled a previously unrecognized role of neutrophils in determining the functional outcome of antigen-specific T-cell responses, effect that is dependent upon the interaction of neutrophils with antigen-presenting cells.

Helicobacter-induced inflammatory bowel disease in IL-10- and T cell-deficient mice

2001 ◽  
Vol 281 (3) ◽  
pp. G764-G778 ◽  
Author(s):  
Andrew Burich ◽  
Robert Hershberg ◽  
Kim Waggie ◽  
Weiping Zeng ◽  
Thea Brabb ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Bowel Disease ◽  
Wild Type ◽  
Immunodeficient Mice ◽  
Inflammatory Bowel ◽  
Rag 1

Inflammatory bowel disease (IBD) is thought to result from a dysregulated mucosal immune response to luminal microbial antigens, with T lymphocytes mediating the colonic pathology. Infection with Helicobacter spp has been reported to cause IBD in immunodeficient mice, some of which lack T lymphocytes. To further understand the role of T cells and microbial antigens in triggering IBD, we infected interleukin (IL)-10−/−, recombinase-activating gene (Rag)1−/−, T-cell receptor (TCR)-α−/−, TCR-β−/−, and wild-type mice with Helicobacter hepaticus or Helicobacter bilis and compared the histopathological IBD phenotype. IL-10−/−mice developed severe diffuse IBD with either H. bilis or H. hepaticus, whereas Rag1−/−, TCR-α−/−, TCR-β−/−, and wild-type mice showed different susceptibilities to Helicobacter spp infection. Proinflammatory cytokine mRNA expression was increased in the colons of Helicobacter-infected IL-10−/−and TCR-α−/−mice with IBD. These results confirm and extend the role of Helicobacter as a useful tool for investigating microbial-induced IBD and show the importance, but not strict dependence, of T cells in the development of bacterial-induced IBD.

scholarly journals FXR mediates T cell-intrinsic responses to reduced feeding during infection

2020 ◽  
Vol 117 (52) ◽  
pp. 33446-33454
Author(s):  
Clarissa Campbell ◽  
Francois Marchildon ◽  
Anthony J. Michaels ◽  
Naofumi Takemoto ◽  
Joris van der Veeken ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Cell Survival ◽  
Sickness Behavior ◽  
Effector T Cells ◽  
Farnesoid X Receptor ◽  
Limiting Nutrient ◽  
Cognate Antigen

Reduced nutrient intake is a widely conserved manifestation of sickness behavior with poorly characterized effects on adaptive immune responses. During infectious challenges, naive T cells encountering their cognate antigen become activated and differentiate into highly proliferative effector T cells. Despite their evident metabolic shift upon activation, it remains unclear how effector T cells respond to changes in nutrient availability in vivo. Here, we show that spontaneous or imposed feeding reduction during infection decreases the numbers of splenic lymphocytes. Effector T cells showed cell-intrinsic responses dependent on the nuclear receptor Farnesoid X Receptor (FXR). Deletion of FXR in T cells prevented starvation-induced loss of lymphocytes and increased effector T cell fitness in nutrient-limiting conditions, but imparted greater weight loss to the host. FXR deficiency increased the contribution of glutamine and fatty acids toward respiration and enhanced cell survival under low-glucose conditions. Provision of glucose during anorexia of infection rescued effector T cells, suggesting that this sugar is a limiting nutrient for activated lymphocytes and that alternative fuel usage may affect cell survival in starved animals. Altogether, we identified a mechanism by which the host scales immune responses according to food intake, featuring FXR as a T cell-intrinsic sensor.

scholarly journals An Essential Role for Interleukin 10 in the Function of Regulatory T Cells That Inhibit Intestinal Inflammation

1999 ◽  
Vol 190 (7) ◽  
pp. 995-1004 ◽  
Author(s):  
Chrystelle Asseman ◽  
Smita Mauze ◽  
Michael W. Leach ◽  
Robert L. Coffman ◽  
Fiona Powrie
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cell Population ◽  
Transforming Growth Factor ◽  
Intestinal Inflammation ◽  
Inflammatory Responses ◽  
Cd4 Cells ◽  
Immunodeficient Mice

A T helper cell type 1–mediated colitis develops in severe combined immunodeficient mice after transfer of CD45RBhigh CD4+ T cells and can be prevented by cotransfer of the CD45RBlow subset. The immune-suppressive activities of the CD45RBlow T cell population can be reversed in vivo by administration of an anti-transforming growth factor β antibody. Here we show that interleukin (IL)-10 is an essential mediator of the regulatory functions of the CD45RBlow population. This population isolated from IL-10–deficient (IL-10−/−) mice was unable to protect from colitis and when transferred alone to immune-deficient recipients induced colitis. Treatment with an anti–murine IL-10 receptor monoclonal antibody abrogated inhibition of colitis mediated by wild-type (WT) CD45RBlow CD4+ cells, suggesting that IL-10 was necessary for the effector function of the regulatory T cell population. Inhibition of colitis by WT regulatory T cells was not dependent on IL-10 production by progeny of the CD45RBhigh CD4+ cells, as CD45RBlow CD4+ cells from WT mice were able to inhibit colitis induced by IL-10−/− CD45RBhigh CD4+ cells. These findings provide the first clear evidence that IL-10 plays a nonredundant role in the functioning of regulatory T cells that control inflammatory responses towards intestinal antigens.

Protection from graft-versus-host disease by HIV-1 envelope protein gp120-mediated activation of human CD4+CD25+ regulatory T cells

Blood ◽  
2009 ◽  
Vol 114 (6) ◽  
pp. 1263-1269 ◽  
Author(s):  
Christian Becker ◽  
Christian Taube ◽  
Tobias Bopp ◽  
Christoph Becker ◽  
Kai Michel ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
Graft Versus Host Disease ◽  
Adenosine Monophosphate ◽  
Host Disease ◽  
Graft Versus Host

AbstractNaturally occurring CD4+CD25+ regulatory T cells (Tregs) represent a unique T-cell lineage that is endowed with the ability to actively suppress immune responses. Therefore, approaches to modulate Treg function in vivo could provide ways to enhance or reduce immune responses and lead to novel therapies. Here we show that the CD4 binding human immunodeficiency virus-1 envelope glycoprotein gp120 is a useful and potent tool for functional activation of human Tregs in vitro and in vivo. Gp120 activates human Tregs by binding and signaling through CD4. Upon stimulation with gp120, human Tregs accumulate cyclic adenosine monophosphate (cAMP) in their cytosol. Inhibition of endogeneous cAMP synthesis prevents gp120-mediated Treg activation. Employing a xenogeneic graft versus host disease model that has been shown to be applicable for the functional analysis of human Tregs in vivo, we further show that a single dose of gp120 is sufficient to prevent lethal graft versus host disease and that the tolerizing effect of gp120 is strictly dependent on the presence of human Tregs and their up-regulation of cAMP upon gp120-mediated activation. Our findings demonstrate that stimulation via the CD4 receptor represents a T-cell receptor–independent Treg activating pathway with potential to induce immunologic tolerance in vivo.

Rap1-GTP Promotes the Generation of Regulatory T Cells in Vivo.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 110-110
Author(s):  
Lequn Li ◽  
Rebecca Greenwald ◽  
Esther M. Lafuente ◽  
Dimitrios Tzachanis ◽  
Alla Berezovskaya ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cd4 Cells

Abstract Elucidating the mechanisms that regulate T cell activation and tolerance in vivo will provide insights into the maintenance of physiologic homeostasis and will facilitate development novel strategies for induction of transplantation tolerance. Transient activation of the small GTPase Rap1 is one of the physiologic consequences of TCR ligation and is mandatory for β1 and β2 integrin-mediated adhesion. In contrast, sustained increase of active Rap1 inhibits T cell activation and IL-2 transcription in vitro. In order to understand the role of Rap1 in the immune responses of the intact host we generated transgenic (Tg) mice, which express the active Rap1 mutant Rap1E63 in T cells. Rap1E63-Tg mice had no defects in thymocyte development or maturation. Rap1E63-Tg thymocytes were capable of activating Ras and Erk1/2 and, compared to wild type (WT) thymocytes, displayed enhanced LFA-1:ICAM-1-mediated adhesion and increased proliferation in response to anti-CD3. Surprisingly, although lymph node and splenic CD4+ cells from the Rap1E63-Tg mice also displayed increased LFA-1:ICAM-1-mediated adhesion, they had significantly impaired activation of Erk1/2 and dramatically reduced proliferation and IL-2 production in response to anti-CD3 and WT antigen presenting cells (APC). The defective responses of CD4+ T cells suggest that Rap1E63-Tg mice may have impaired helper function in vivo. To address this issue we immunized Rap1E63-Tg and WT mice with TNP-OVA, a T-cell dependent antigen. Total IgG, IgG1 and IgG2a were dramatically reduced, indicating that Rap1E63-Tg mice had a defect in immunoglobulin class switching, consistent with defective helper T cell-dependent B cell activation. Because these results suggest that Rap1E63-Tg CD4+ cells may have an anergic phenotype, we tested rechallenge responses. We immunized Rap1E63-Tg and WT mice with TNP-OVA in vivo and subsequently we rechallenged T cells in vitro with WT APC pulsed with OVA. Compared with WT, Rap1E63-Tg T cells had dramatically reduced proliferation, IFN- γ and IL-2 production on rechallenge, findings consistent with T cell anergy. Using suppression subtraction hybridization we determined that Rap1E63 induced mRNA expression of CD103, a marker that defines a potent subset of regulatory T cells (Treg). Strikingly, Rap1E63-Tg mice had a 5-fold increase of CD103+CD25+CD4+ Treg compared to WT mice. Rap1E63-Tg CD103+CD25+CD4+ Treg expressed the highest level of Foxp3 among all T cell subsets and had the most potent inhibitory effect on proliferation and IL-2 production when added into cultures of WT CD4+CD25− cells. Importantly, removal of the CD103+ cells significantly restored Erk1/2 activation, proliferation and IL-2 production of Rap1E63-Tg CD4+ T cells. Generation of CD103+ Treg occurs after thymic development and requires encounter of peripheral autoantigen. Consistent with this, differences in CD103+ Treg were detected only between lymph node and splenic cells and not between thymocytes from Rap1E63-Tg and WT mice. Since generation of CD103+ Treg depends on the strength of TCR signal, these results suggest that by enhancing adhesion, active Rap1 regulates the generation of Treg. Moreover, these results provide evidence that active Rap1 is a potent negative regulator of immune responses in vivo and have significant implications for the development of immune-based therapies geared towards tolerance induction.

scholarly journals Endogenous CD4+ CD25+ Regulatory T Cells Have a Limited Role in the Control of Trypanosoma cruzi Infection in Mice

2006 ◽  
Vol 75 (2) ◽  
pp. 861-869 ◽  
Author(s):  
Joshua Kotner ◽  
Rick Tarleton
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Trypanosoma Cruzi ◽  
Immune Responses ◽  
Chagas Disease ◽  
Treg Cells ◽  
Foxp3 Mrna ◽  
Cell Effector

ABSTRACT Infection with the protozoan parasite Trypanosoma cruzi results in a robust and multifaceted immune response that controls parasite load but is unable to completely clear infection, resulting in parasite persistence and a chronic illness known as Chagas' disease in humans. The severity of Chagas' disease is correlated with persistent parasitism of muscle, neuronal, and gut tissues. The natural immunomodulatory function of endogenous CD4+ CD25+ regulatory T cells (Treg cells) to limit hyperactive immune responses may be exploited by microbes to persist despite host responses. In this study, we show that Treg cells are not necessary for T. cruzi evasion of immune responses during acute or chronic infection. In vivo anti-CD25 monoclonal antibody-mediated depletion of Treg cells from mice prior to challenge with a lethal strain or prior to and during acute infection with a nonlethal strain of parasite neither improved nor worsened the outcome of immune responses: differences in parasitemia, kinetics of antigen-specific CD8+ T-cell expansion, and CD8+ T-cell effector function (both in vivo and ex vivo) were of similar magnitudes for both depleted and control groups. Furthermore, depletion of CD25+ cells from chronically infected mice did not enhance immune responses of muscle-derived CD8+ T cells, nor could FoxP3 mRNA/scurfin-expressing leukocytes be isolated from muscle tissue. Based on the results of this study, it is concluded that Treg cells do not appear to play a major role in regulating CD8+ T-cell effector responses during the acute phase of infection or in the muscles of mice during chronic T. cruzi infection.

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