scholarly journals Interleukin 2 Signaling Is Required for CD4+ Regulatory T Cell Function

2002 ◽  
Vol 196 (6) ◽  
pp. 851-857 ◽  
Author(s):  
Gláucia C. Furtado ◽  
Maria A. Curotto de Lafaille ◽  
Nino Kutchukhidze ◽  
Juan J. Lafaille
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Regulatory T Cell ◽  
Cd4 T Cells ◽  
Cell Function ◽  
Interleukin 2 ◽  
Cell Activity ◽  
Protective Function ◽  
And Function

Mice deficient in interleukin (IL)-2 production or the IL-2 receptor α or β chains develop a lethal autoimmune syndrome. CD4+ regulatory T cells have been shown to prevent autoimmune diseases, allograft rejection, and to down-regulate antibody responses against foreign antigens. To assess the role of IL-2 in the generation and function of regulatory T cells, we transferred CD4+ T cells from mice genetically deficient in IL-2 or IL-2Rα (CD25) expression. A small number of splenic or thymic CD4+ T cells from IL-2 knockout mice can protect mice from spontaneous experimental autoimmune encephalomyelitis (EAE). In contrast, splenic or thymic CD4+ T cells from CD25 knockout donor mice conferred little or no protection. We conclude that T cells with regulatory potential can develop, undergo thymic selection, and migrate to the peripheral lymphoid organs in the absence of IL-2, and do not protect from disease by means of IL-2 secretion. However, IL-2 signaling in regulatory T cells is essential for their protective function. Altogether, our results favor a model whereby IL-2 induces regulatory T cell activity.

scholarly journals Endogenous CD4+ CD25+ Regulatory T Cells Play No Apparent Role in the Acute Humoral Response to Intact Streptococcus pneumoniae

2005 ◽  
Vol 73 (7) ◽  
pp. 4427-4431 ◽  
Author(s):  
Katherine S. Lee ◽  
Goutam Sen ◽  
Clifford M. Snapper
Keyword(s):  
T Cells ◽  
Streptococcus Pneumoniae ◽  
T Cell ◽  
Regulatory T Cells ◽  
Regulatory T Cell ◽  
Cell Function ◽  
Interleukin 2 ◽  
Tumor Necrosis Factor Receptor ◽  
Negative Control ◽  
Cell Mediated Immunity

ABSTRACT Immunoglobulin G (IgG) antiprotein and antipolysaccharide responses to intact Streptococcus pneumoniae are CD4+-T-cell dependent and therefore might be under the negative control of CD4+ CD25+ regulatory T cells. Injection of anti-interleukin 2 receptor α (anti-IL-2Rα) MAb to deplete regulatory T cells, injection of agonistic MAb against glucocorticoid-induced tumor necrosis factor receptor family-related protein to inhibit regulatory-T-cell function, and adoptive transfer of regulatory-T-cell-depleted CD4+ T cells into athymic nude mice each had no effect on either the primary or secondary protein- or polysaccharide-specific IgG response to intact S. pneumoniae. Surprisingly, anti-IL-2Rα MAb also had no effect on the IgG response to intact S. pneumoniae in MyD88−/− mice or to a soluble protein-polysaccharide conjugate injected into wild-type mice in the absence of adjuvant. Collectively, these data are the first to suggest that, in contrast to their role in limiting chronic cell-mediated immunity, regulatory T cells may play no significant role in an acute humoral immune response to an intact extracellular bacterial pathogen.

scholarly journals CD4+ regulatory T cells require CTLA-4 for the maintenance of systemic tolerance

2009 ◽  
Vol 206 (2) ◽  
pp. 421-434 ◽  
Author(s):  
Randall H. Friedline ◽  
David S. Brown ◽  
Hai Nguyen ◽  
Hardy Kornfeld ◽  
JinHee Lee ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cell Function ◽  
Cytotoxic T Lymphocyte ◽  
Critical Role ◽  
Lymphoproliferative Disease ◽  
In Trans ◽  
And Function

Cytotoxic T lymphocyte antigen-4 (CTLA-4) plays a critical role in negatively regulating T cell responses and has also been implicated in the development and function of natural FOXP3+ regulatory T cells. CTLA-4–deficient mice develop fatal, early onset lymphoproliferative disease. However, chimeric mice containing both CTLA-4–deficient and –sufficient bone marrow (BM)–derived cells do not develop disease, indicating that CTLA-4 can act in trans to maintain T cell self-tolerance. Using genetically mixed blastocyst and BM chimaeras as well as in vivo T cell transfer systems, we demonstrate that in vivo regulation of Ctla4−/− T cells in trans by CTLA-4–sufficient T cells is a reversible process that requires the persistent presence of FOXP3+ regulatory T cells with a diverse TCR repertoire. Based on gene expression studies, the regulatory T cells do not appear to act directly on T cells, suggesting they may instead modulate the stimulatory activities of antigen-presenting cells. These results demonstrate that CTLA-4 is absolutely required for FOXP3+ regulatory T cell function in vivo.

scholarly journals Characterizing T Cells in SCID Patients Presenting with Reactive or Residual T Lymphocytes

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Atar Lev ◽  
Amos J. Simon ◽  
Luba Trakhtenbrot ◽  
Itamar Goldstein ◽  
Meital Nagar ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cell Function ◽  
Severe Combined Immunodeficiency ◽  
Cell Activity ◽  
Mhc Ii ◽  
Cell Functions ◽  
Circulating T Cells

Introduction. Patients with severe combined immunodeficiency (SCID) may present with residual circulating T cells. While all cells are functionally deficient, resulting in high susceptibility to infections, only some of these cells are causing autoimmune symptoms.Methods. Here we compared T-cell functions including the number of circulating CD3+T cells,in vitroresponses to mitogens, T-cell receptor (TCR) repertoire, TCR excision circles (TREC) levels, and regulatory T cells (Tregs) enumeration in several immunodeficinecy subtypes, clinically presenting with nonreactive residual cells (MHC-II deficiency) or reactive cells. The latter includes patients with autoreactive clonal expanded T cell and patients with alloreactive transplacentally maternal T cells.Results. MHC-II deficient patients had slightly reduced T-cell function, normal TRECs, TCR repertoires, and normal Tregs enumeration. In contrast, patients with reactive T cells exhibited poor T-cell differentiation and activity. While the autoreactive cells displayed significantly reduced Tregs numbers, the alloreactive transplacentally acquired maternal lymphocytes had high functional Tregs.Conclusion. SCID patients presenting with circulating T cells show different patterns of T-cell activity and regulatory T cells enumeration that dictates the immunodeficient and autoimmune manifestations. We suggest that a high-tolerance capacity of the alloreactive transplacentally acquired maternal lymphocytes represents a toleration advantage, yet still associated with severe immunodeficiency.

Defective T-helper cell function after T-cell–depleting therapy affecting naive and memory populations

Blood ◽  
2002 ◽  
Vol 99 (11) ◽  
pp. 4053-4062 ◽  
Author(s):  
Andreas Heitger ◽  
Patricia Winklehner ◽  
Petra Obexer ◽  
Johannes Eder ◽  
Claudia Zelle-Rieser ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Mononuclear Cells ◽  
Cell Function ◽  
Interleukin 2 ◽  
T Helper Cell ◽  
Helper Cell ◽  
High Dose ◽  
T Helper

Impaired T-cell function after T-cell– depleting (TCD) therapy has been hypothesized to be related to a transient predominance of extrathymically expanding memory T cells. To test whether after TCD therapy the naive T-helper cell population is functionally intact, the in vitro immune response of CD4+CD45RA+ (naive) and of CD4+CD45RA− (memory) cells to polyclonal mitogens (immobilized anti-CD3, phytohemagglutinin) was analyzed by flow cytometry in 22 pediatric patients after high-dose chemotherapy (including 5 after autologous and 5 after allogeneic stem cell support). At 1 to 3 months after TCD therapy, patient samples showing decreased lymphoproliferative responses also showed a reduced induction of the early activation marker CD69 by CD4+ T cells from 4 to 72 hours after stimulation even when supplemented with exogenous interleukin-2. This defect affected CD4+CD45RA− cells, but, strikingly, also CD4+CD45RA+ cells, including samples in which CD4+CD45RA+ cells were more than 90/μL, thus indicating ongoing thymopoiesis. Histogram analyses showed the median peak channel of CD69 in control CD4+CD45RA+cells rising 98-fold (median) but only 28-fold in patient cells (P < .0001). Apoptosis as detected by annexin V staining was increased in resting patient CD4+ T cells (25% versus 6%) and also affected CD4+CD45RA+ cells (12% versus 5%, P < .01). When peripheral blood mononuclear cells (PBMCs) were enriched for T cells, stimulatory responses of CD4+ cells and of CD4+CD45RA+ cells markedly improved. Thus, after TCD therapy suppressor factors contained in the non–T-cell fraction of PBMCs may affect T-helper cells irrespective of their naive or memory phenotype thus extending T-cell dysfunction to the presumably thymus-dependently regenerated T cells.

scholarly journals Fine-Tuning of Regulatory T Cell Function: The Role of Calcium Signals and Naive Regulatory T Cells for Regulatory T Cell Deficiency in Multiple Sclerosis

2013 ◽  
Vol 190 (10) ◽  
pp. 4965-4970 ◽  
Author(s):  
Alexander Schwarz ◽  
Marijana Schumacher ◽  
Daniel Pfaff ◽  
Kai Schumacher ◽  
Sven Jarius ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Regulatory T Cell ◽  
Cell Function ◽  
Fine Tuning ◽  
Calcium Signals ◽  
T Cell Function

Regulatory T-cells and cAMP suppress effector T-cells independently of PKA–CREM/ICER: a potential role for Epac

2013 ◽  
Vol 456 (3) ◽  
pp. 463-473 ◽  
Author(s):  
Amanda G. Vang ◽  
William Housley ◽  
Hongli Dong ◽  
Chaitali Basole ◽  
Shlomo Z. Ben-Sasson ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Regulatory T Cell ◽  
Potential Role ◽  
Cell Function ◽  
Effector T Cells ◽  
Immune Control ◽  
Effector T Cell ◽  
Camp Signalling

Immune control of effector T-cell function can be mediated by cAMP signalling and regulatory T-cell action independently of the PKA–CREM/ICER signalling pathway. EPAC may act as an alternative cAMP effector in this process.

Human CD4+CD25+ cells: a naturally occurring population of regulatory T cells

Blood ◽  
2001 ◽  
Vol 98 (9) ◽  
pp. 2736-2744 ◽  
Author(s):  
Wan Fai Ng ◽  
Phillip J. Duggan ◽  
Frederique Ponchel ◽  
Giuseppe Matarese ◽  
Giovanna Lombardi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cd4 T Cells ◽  
Interleukin 2 ◽  
Notch Pathway ◽  
Regulatory Function ◽  
Cell Contact ◽  
Transcriptional Level ◽  
Fetal Life

Abstract Despite thymic deletion of cells with specificity for self-antigens, autoreactive T cells are readily detectable in the normal T-cell repertoire. In recent years, a population of CD4+ T cells that constitutively express the interleukin-2 receptor-α chain, CD25, has been shown to play a pivotal role in the maintenance of self-tolerance in rodent models. This study investigated whether such a regulatory population exists in humans. A population of CD4+CD25+ T cells, taken from the peripheral blood of healthy individuals and phenotypically distinct from recently activated CD4+ T cells, was characterized. These cells were hyporesponsive to conventional T-cell stimuli and capable of suppressing the responses of CD4+CD25− T cells in vitro. Addition of exogenous interleukin-2 abrogated the hyporesponsiveness and suppressive effects of CD4+CD25+ cells. Suppression required cell-to-cell contact but did not appear to be via the inhibition of antigen-presenting cells. In addition, there were marked changes in the expression of Notch pathway molecules and their downstream signaling products at the transcriptional level, specifically in CD4+CD25+ cells, suggesting that this family of molecules plays a role in the regulatory function of CD4+CD25+ cells. Cells with similar phenotype and function were detected in umbilical venous blood from healthy newborn infants. These results suggest that CD4+CD25+ cells represent a population of regulatory T cells that arise during fetal life. Comparison with rodent CD4+CD25+ cells suggests that this population may play a key role in the prevention of autoimmune diseases in humans.

scholarly journals Enforced IL-10 Expression Confers Type 1 Regulatory T Cell (Tr1) Phenotype and Function to Human CD4+ T Cells

2012 ◽  
Vol 20 (9) ◽  
pp. 1778-1790 ◽  
Author(s):  
Grazia Andolfi ◽  
Georgia Fousteri ◽  
Maura Rossetti ◽  
Chiara F Magnani ◽  
Tatiana Jofra ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cell ◽  
Cd4 T Cells ◽  
And Function

scholarly journals Formaldehyde exposure induces regulatory T cell-mediated immunosuppression via calcineurin-NFAT signalling pathway

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Jeongsik Park ◽  
Hyo-Seon Yang ◽  
Mi-Kyung Song ◽  
Dong Im Kim ◽  
Kyuhong Lee
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
Mrna Expression ◽  
Regulatory T Cell ◽  
Cell Activity ◽  
Helper T Cells ◽  
Dependent Manner ◽  
Dose Dependent

Abstract In this study, we investigated the effects of Formaldehyde (FA) exposure on splenic immune responses wherein helper T cells become activated and differentiate into effector T and regulatory T cells. BALB/c mice were exposed to two FA concentrations (1.38 mg/m3 and 5.36 mg/m3) for 4 h/day and 5 days/week for 2 weeks. FA-induced immune responses were examined by the production of cytokines, expression of mRNAs, and distributions of helper T cells and regulatory T cells. Moreover, expression of calcineurin and NFATs, regulatory T cell-related signalling proteins, were evaluated. FA exposure suppressed Th2-, Th1-, and Th17-related splenic cytokines in a dose-dependent manner. mRNA expression of splenic cytokines was also decreased by FA exposure, which correlated with decreased cytokine expression. In parallel, FA exposure promoted T cell differentiation into regulatory T cells in a dose-dependent manner supported by the expression of calcineurin and NFAT1. Taken together, our results indicated that FA exposure increases the number of regulatory T cells via calcineurin-NFAT signalling, thereby leading to effector T cell activity suppression with decreased T cell-related cytokine secretion and mRNA expression. These findings provide insight into the mechanisms underlying the adverse effects of FA and accordingly have general implications for human health, particularly in occupational settings.

Suppression of the Immune Response to Human FVIII with FVIII Transgene Modified Tolerogenic Dendritic Cells in Hemophilic Mice

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 591-591
Author(s):  
Rui-Jun Su ◽  
Angela Epp ◽  
Xiaoping Wu ◽  
Neil Josephson
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Regulatory T Cell ◽  
Cd4 T Cells ◽  
Hemophilia A ◽  
Tolerogenic Dendritic Cells

Abstract The development of anti-factor VIII (FVIII) inhibitory antibodies is currently the most significant complication of FVIII replacement therapy in the management of patients with hemophilia A. Infusion of in vitro generated tolerogenic dendritic cells (tDCs) loaded with foreign antigen has been shown to promote durable antigen-specific tolerance in vivo through mechanisms that involve the induction of regulatory T cells. In this study we evaluated the ability of tDCs transduced with a human B domain deleted FVIII transgene-expressing foamy virus (FV) vector to modulate the immune response to human FVIII in both naïve and pre-immunized hemophilia A mice. The tDCs were generated by flow sorting the population of CD11clowCD45RBhigh cells produced in culture of lineage negative bone marrow cells in RPMI1640/10%FBS supplemented with IL-10 and the neural peptides VIP and PACAP38. Expression of co-stimulatory molecules CD80 and CD86 and MHC Class II was negative or low on the generated tDCs and these cells remained un-activated even after stimulation with LPS or transduction by FV vectors. These tDCs produced low levels of IL-6 and TNF-α, and high level of IL-10. Furthermore, co-culture of the vector transduced tDCs with FVIII stimulated effector T cells (Teffs) resulted in decreased proliferation of Teffs and reduced secretion of IFN-γ and IL-2. In the cultures with the transduced tDCs there was also an increase in the number of apoptotic Teffs. Naïve Balb/c hemophilia A mice were treated with 2 weekly infusions of FVIII vector transduced tDCs (tDC-F8), control tDCs (tDCs-Ctrl), or no cells (Neg-Ctrl) prior to being challenged with four weekly intravenous doses of 0.2 μg rhFVIII. Following immunization the total cellularity and weights of spleens harvested from tDC-F8 mice were consistently half that of spleens from either tDC-Ctrl or Neg-Ctrl mice. Furthermore, inhibitor titers in tDC-F8 mice were 60–61% lower than either Neg-Ctrl or tDC-Ctrl mice (p < 0.05 compared to both controls). The regulatory T cell related markers FOXP3, CD25, CD103, CTLA4 and GITR were all up-regulated on splenic CD4+ T cells from tDC-F8 mice and the CD4+ T cell proliferation response to FVIII stimulation in splenocytes from tDC-F8 mice was suppressed by approximately 90%. Moreover, the rate of apoptosis in splenic T cells from tDC-F8 mice was 33% higher than splenic T cells from either Neg-Ctrl or tDC-Ctrl mice. In pre-immunized mice, treatment with 4 weekly infusions of FVIII vector transduced tDCs lowered inhibitor titers by 54% compared to no treatment controls (p < 0.05). In contrast, treatment with untransduced tDCs had no significant effect on the inhibitor titers of pre-immunized mice. Importantly, adoptive transfer of CD4+ T cells from tDC-8 mice produced suppression of the immune response to FVIII in subsequently immunized naïve secondary recipients.. In summary, these data indicate that FVIII vector transduced tDCs are useful in suppressing the immune response to FVIII in hemophilia A mice and suggest that regulatory T cells play a role in the induced immune modulation. More in vivo studies are in progress to confirm the durability of these effects. Future studies will also focus on isolating and characterizing the regulatory T cell populations induced by in vivo administration of transgene modified tDCs.

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