scholarly journals Homeostatic maintenance of natural Foxp3+ CD25+ CD4+ regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization

2005 ◽  
Vol 201 (5) ◽  
pp. 723-735 ◽  
Author(s):  
Ruka Setoguchi ◽  
Shohei Hori ◽  
Takeshi Takahashi ◽  
Shimon Sakaguchi
Keyword(s):  
T Cells ◽  
T Cell ◽  
Autoimmune Disease ◽  
Regulatory T Cells ◽  
Cd4 T Cells ◽  
Wide Spectrum ◽  
Physiological State ◽  
Predisposing Factor ◽  
Activated T Cells ◽  
Similar Treatment

Interleukin (IL)-2 plays a crucial role in the maintenance of natural immunologic self-tolerance. Neutralization of circulating IL-2 by anti–IL-2 monoclonal antibody for a limited period elicits autoimmune gastritis in BALB/c mice. Similar treatment of diabetes-prone nonobese diabetic mice triggers early onset of diabetes and produces a wide spectrum of T cell–mediated autoimmune diseases, including gastritis, thyroiditis, sialadenitis, and notably, severe neuropathy. Such treatment selectively reduces the number of Foxp3-expressing CD25+ CD4+ T cells, but not CD25− CD4+ T cells, in the thymus and periphery of normal and thymectomized mice. IL-2 neutralization inhibits physiological proliferation of peripheral CD25+ CD4+ T cells that are presumably responding to normal self-antigens, whereas it is unable to inhibit their lymphopenia-induced homeostatic expansion in a T cell–deficient environment. In normal naive mice, CD25low CD4+ nonregulatory T cells actively transcribe the IL-2 gene and secrete IL-2 protein in the physiological state. IL-2 is thus indispensable for the peripheral maintenance of natural CD25+ CD4+ regulatory T cells (T reg cells). The principal physiological source of IL-2 for the maintenance of T reg cells appears to be other T cells, especially CD25low CD4+ activated T cells, which include self-reactive T cells. Furthermore, impairment of this negative feedback loop via IL-2 can be a cause and a predisposing factor for autoimmune disease.

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 IL10-Deficiency in CD4+ T Cells Exacerbates the IFNγ and IL17 Response During Bacteria Induced Colitis

2015 ◽  
Vol 36 (4) ◽  
pp. 1259-1273 ◽  
Author(s):  
Virginia Seiffart ◽  
Julia Zoeller ◽  
Robert Klopfleisch ◽  
Munisch Wadwa ◽  
Wiebke Hansen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Intestinal Inflammation ◽  
Cd4 T Cell ◽  
Intestinal Homeostasis ◽  
Crypt Hyperplasia

Background/Aims: IL10 is a key inhibitor of effector T cell activation and a mediator of intestinal homeostasis. In addition, IL10 has emerged as a key immunoregulator during infection with various pathogens, ameliorating the excessive T-cell responses that are responsible for much of the immunopathology associated with the infection. Because IL10 plays an important role in both intestinal homeostasis and infection, we studied the function of IL10 in infection-associated intestinal inflammation. Methods: Wildtype mice and mice deficient in CD4+ T cell-derived or regulatory T cells-derived IL10 were infected with the enteric pathogen Citrobacter (C.) rodentium and analyzed for the specific immune response and pathogloy in the colon. Results: We found that IL10 expression is upregulated in colonic tissue after infection with C. rodentium, especially in CD4+ T cells, macrophages and dendritic cells. Whereas the deletion of IL10 in regulatory T cells had no effect on C. rodentium induced colitis, infection of mice deficient in CD4+ T cell-derived IL10 exhibited faster clearance of the bacterial burden but worse colitis, crypt hyperplasia, and pathology than did WT mice. In addition, the depletion of CD4+ T cell-derived IL10 in infected animals was accompanied by an accelerated IFNγ and IL17 response in the colon. Conclusion: Thus, we conclude that CD4+ T cell-derived IL10 is strongly involved in the control of C. rodentium-induced colitis. Interference with this network could have implications for the treatment of infection-associated intestinal inflammation.

scholarly journals Role of Exosomes in the Regulation of T-cell Mediated Immune Responses and in Autoimmune Disease

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 154 ◽  
Author(s):  
Alberto Anel ◽  
Ana Gallego-Lleyda ◽  
Diego de Miguel ◽  
Javier Naval ◽  
Luis Martínez-Lostao
Keyword(s):  
T Cells ◽  
T Cell ◽  
Autoimmune Disease ◽  
Immune Responses ◽  
T Regulatory Cells ◽  
Inflammatory Diseases ◽  
Activated T Cells ◽  
Regulatory Processes ◽  
Activation Induced Cell Death

: T-cell mediated immune responses should be regulated to avoid the development of autoimmune or chronic inflammatory diseases. Several mechanisms have been described to regulate this process, namely death of overactivated T cells by cytokine deprivation, suppression by T regulatory cells (Treg), induction of expression of immune checkpoint molecules such as CTLA-4 and PD-1, or activation-induced cell death (AICD). In addition, activated T cells release membrane microvesicles called exosomes during these regulatory processes. In this review, we revise the role of exosome secretion in the different pathways of immune regulation described to date and its importance in the prevention or development of autoimmune disease. The expression of membrane-bound death ligands on the surface of exosomes during AICD or the more recently described transfer of miRNA or even DNA inside T-cell exosomes is a molecular mechanism that will be analyzed.

scholarly journals Elevated frequencies of highly activated CD4+ T cells in HIV+ patients developing immune reconstitution inflammatory syndrome

Blood ◽  
2010 ◽  
Vol 116 (19) ◽  
pp. 3818-3827 ◽  
Author(s):  
Lis R. V. Antonelli ◽  
Yolanda Mahnke ◽  
Jessica N. Hodge ◽  
Brian O. Porter ◽  
Daniel L. Barber ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Immune Reconstitution Inflammatory Syndrome ◽  
Cd4 T Cells ◽  
Immune Reconstitution ◽  
Interferon Γ ◽  
Effector Memory ◽  
Hiv Patients ◽  
Inflammatory Syndrome

Abstract Immune reconstitution inflammatory syndrome (IRIS) is a considerable problem in the treatment of HIV-infected patients. To identify immunologic correlates of IRIS, we characterized T-cell phenotypic markers and serum cytokine levels in HIV patients with a range of different AIDS-defining illnesses, before and at regular time points after initiation of antiretroviral therapy. Patients developing IRIS episodes displayed higher frequencies of effector memory, PD-1+, HLA-DR+, and Ki67+ CD4+ T cells than patients without IRIS. Moreover, PD-1+ CD4+ T cells in IRIS patients expressed increased levels of LAG-3, CTLA-4, and ICOS and had a Th1/Th17 skewed cytokine profile upon polyclonal stimulation. Elevated PD-1 and Ki67 expression was also seen in regulatory T cells of IRIS patients. Furthermore, IRIS patients displayed higher serum interferon-γ, compared with non-IRIS patients, near the time of their IRIS events and higher serum interleukin-7 levels, suggesting that the T-cell populations are also exposed to augmented homeostatic signals. In conclusion, our findings indicate that IRIS appears to be a predominantly CD4-mediated phenomenon with reconstituting effector and regulatory T cells showing evidence of increased activation from antigenic exposure. These studies are registered online at http://clinicaltrials.gov as NCT00557570 and NCT00286767.

The ICOS:ICOSL Costimulatory Pathway Plays an Important Role in GVHD and Bone Marrow (BM) Graft Rejection.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 591-591 ◽  
Author(s):  
Patricia Taylor ◽  
Angela Panoskaltsis-Mortari ◽  
Gordon Freeman ◽  
Arlene Sharpe ◽  
Randolph Noelle ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Family Member ◽  
Cd8 T Cells ◽  
Graft Rejection ◽  
Cd4 T Cells ◽  
Fluorescent Protein ◽  
Wild Type ◽  
Activated T Cells ◽  
Effector Cells

Abstract ICOS, a CD28/CTLA-4 family member, is expressed on activated T cells. ICOS Ligand, a B7 family member, is constitutively expressed on B cells, monocytes and some T cells. Through the use of blocking anti-ICOS mAb and ICOS deficient (−/−) mice, we found that ICOS:ICOSL interactions play an important role in GVHD and BM graft rejection. Anti-ICOS mAb (given d-1 to d28 post BMT) significantly delayed or reduced mortality at 2 different T cell doses in a full MHC-disparate GVHD model. ICOS−/− T cells led to delayed or reduced mortality at 3 different cell doses compared to wild-type T cells. ICOS−/− CD4+ or CD8+ T cells infused into class II- or class I-disparate recipients, respectively, revealed that ICOS:ICOSL interactions regulate both CD4+ and CD8+ T cell alloresponses. Anti-ICOS inhibited GVHD in a CD28-independent fashion. Anti-ICOS inhibited GVHD mediated by either stat 4−/− or stat 6−/− T cells indicating that the ICOS pathway regulates both Th2 and Th1-mediated GVHD. In contrast to blockade of the B7:CD28/CTLA-4, CD40L:CD40 or the OX40:OX40L pathway, anti-ICOS mAb inhibited GVHD even when delayed until d5 post BMT, a time when substantial T cell expansion has occurred. A TCR transgenic model of GVHD was used to further study effects of ICOS:ICOSL blockade. All CB6 F1 recipients of anti-host alloreactive 2C CD8+ and TEa CD4+ T cells succumbed to GVHD mortality by d18 after transfer of cells. In contrast, 88% of anti-ICOS-treated mice survived long-term. Evaluation of spleens early after transplant revealed that anti-ICOS mAb reduced the number of TEa CD4+ cells by 44% and 2C CD8+ cells by 83%. Green fluorescent protein (GFP) 2C CD8+ and GFP TEa CD4+ T cells were infused into irradiated CB6 F1 mice and irrelevant or anti-ICOS mAb was administered. Mice were imaged on d4, 7 and 12 after T cell transfer. By d7, pronounced infiltration of GFP+ cells was noted in the peripheral and mesenteric LN, spleen, Peyer’s patches (PP), skin, gingiva, liver, kidney, lung, ileum, and colon of GVHD control mice. In contrast, there were fewer GFP+ cells in the spleen, ileum, colon, kidney, lung, skin and gingiva of anti-ICOS-treated mice, although there was no decrease in GFP+ cells in LNs or PP. To study the role of host ICOS expression in BM graft rejection, wild-type or ICOS−/− mice were sublethally irradiated and given allogeneic BM and evaluated for donor chimerism at 6 weeks post BMT. Five of 10 wild type mice engrafted (ave − 26% donor) in contrast to all 10 of ICOS−/− mice (ave − 71% donor). Collectively, these data indicate that ICOS:ICOSL interactions play an important role in GVHD, whether mediated by CD4+ Th1 or Th2 T cells or CD8+ T cells. Importantly, blockade of ICOS:ICOSL after initiation of alloresponses inhibited GVHD, in contrast to blockade of other costimulatory pathways, suggesting that the ICOS pathway may be a novel therapeutic target in primed transplantation situations. Anti-ICOS interfered with expansion of donor T cells in the spleen early after transplant and reduced the number of effector cells in several GVHD target tissues. These data suggest this pathway may be indicated for therapeutic targeting for the inhibition of GVHD and BM graft rejection.

Dendritic Cell-Induced T Cell Non-Responsiveness Is Mediated by FOXP3+ and TGF-beta+IL-10+ CD4+ T Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3891-3891
Author(s):  
Zwi N. Berneman ◽  
Nathalie Cools ◽  
Viggo F.I. Van Tendeloo ◽  
Marc Lenjou ◽  
Griet Nijs ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
T Cell Immunity ◽  
Tgf Beta ◽  
Cell Immunity

Abstract Dendritic cells (DC), the professional antigen presenting cells of the immune system, exert important functions both in induction of T cell immunity as well as of tolerance. Previously, it was accepted that the main function of immature DC (iDC) in their in vivo steady state condition is to maintain peripheral tolerance to self-antigens and that these iDC mature upon encounter of so-called danger signals and subsequently promote T cell immunity. However, a growing body of experimental evidence now indicates that traditional DC maturation can no longer be used to distinguish between tolerogenic and immunogenic properties of DC. In this study, we compared the in vitro stimulatory capacity of immature DC (iDC), cytokine cocktail-matured DC (CC-mDC) and poly I:C-matured DC (pIC-mDC) in the absence and presence of antigen. All investigated DC types could induce at least 2 subsets of regulatory T cells. We observed a significant increase in both the number of functionally suppressive transforming growth factor (TGF)-beta+ interleukin (IL)-10+ T cells as well as of CD4+CD25+FOXP3+ T cells within DC/T cell co-cultures as compared to T cell cultures without DC. The induction of these regulatory T cells correlates with in vitro T cell non-responsiveness after co-culture with iDC and CC-mDC, while stimulation with pIC-mDC resulted in reproducible cytomegalovirus pp65 or influenza M1 matrix peptide-specific T cell activation as compared to control cultures in the absence of DC. In addition, the T cell non-responsiveness after stimulation with iDC was shown to be mediated by TGF-beta and IL-10. Moreover, the suppressive capacity of CD4+ T cells activated by iDC and CC-mDC was shown to be transferable when these CD4+ T cells were added to an established T cell response. In contrast, addition of CD4+ T cells stimulated by pIC-mDC made responder T cells refractory to their suppressive activity. In conclusion, we hypothesize that DC have a complementary role in inducing both regulatory T cells and effector T cells, where the final result of antigen-specific T cell activation will depend on the activation state of the DC. This emphasizes the need for proper DC activation when T cell immunity is the desired effect, especially when used in clinical trials.

Regulatory T Cells Are Not Required for Prevention of RBC-Specific Autoantibody Generation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 568-568
Author(s):  
Krystalyn E. Hudson ◽  
James C. Zimring
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cd4 T Cells ◽  
T Cell Tolerance ◽  
Cell Tolerance ◽  
Tolerance Mechanisms ◽  
Antibody Treatment ◽  
Isotype Control

Introduction: Loss of humoral tolerance to red blood cell (RBC) antigens may lead to the generation of pathogenic autoantibodies and result in autoimmune hemolytic anemia (AIHA), a severe and potentially fatal disease. Failure of tolerance to RBC antigens occurs with considerable frequency (1-3 cases/1,000 adults) and prevalence of AIHA is as high as 30% in persons with compromised B and/or T cell tolerance mechanisms. However, RBC-specific tolerance mechanisms are poorly understood. To elucidate the immune tolerances to RBC autoantigens, we utilized HOD mice. The HOD mouse expresses an RBC-specific transgene consisting of hen egg lysozyme (HEL), ovalbumin (OVA), and Duffy. Using the HOD model, we previously demonstrated B cell tolerance to RBC-specific HOD antigen is incomplete; however, T cell tolerance is stringent. HOD mice have similar detectable frequencies of HOD-specific CD4+ T cells compared to B6 mice. Although present, autoreactive HOD-specific CD4+ T cells are non-functional. Circumventing T cell tolerance by adoptive transfer, HOD mice make high titer anti-HOD autoantibodies in vivo. Thus, despite the presence of autoreactive B cells, no HOD-reactive antibodies are detectable unless CD4+ T cells are given, indicating T cell tolerance is a stopgap to autoimmunity. Methods: Leukocytes from C57BL/6 (B6) and HOD mice were harvested and OVA-specific CD4+ T cell responses were assessed by tetramer-pulldown assays with pooled tetramers I-Ab-OVA 329-337/326-334. Isolated cells were stained for surface and intracellular markers and analyzed via flow cytometry. For in vivo analysis, mice were treated with 300ug anti-CD25 (clone PC-61) depleting antibody or isotype control; a subset of antibody-treated mice was immunized with OVA/CFA. Antibodies bound to HOD RBCs were determined by direct antibody test. Anti-HOD antibodies were quantified by indirect immunofluorescence using HOD RBCs as targets. Results: Tetramer pull-down assays revealed similar numbers of OVA-reactive CD4+ T cells from HOD and B6 mice (mean 56 and 40, respectively, p = 0.3). However, cell surface and intracellular marker staining demonstrated that HOD mice had higher numbers of OVA-tetramer reactive CD4+ T cells that express regulatory markers CD25 and FoxP3, and exhaustion marker PD1 as compared to control B6 mice. Inhibitory CTLA4 expression was not detectable on OVA-reactive CD4+ T cells from HOD or B6 mice. To test whether regulatory T cells were required for RBC-specific immune tolerance, HOD and B6 mice were treated with CD25 depleting antibody or isotype control antibody. Anti-CD25 antibody treated mice had a significant reduction of CD25+ cells 4 days post treatment (p < 0.001, 2 independent experiments). Similarly, there was a significant reduction in FoxP3+CD25+CD4+ T cells (Tregs) in anti-CD25 treated mice (p < 0.001), compared to isotype. Mice received weekly injections of anti-CD25 or isotype antibody to maintain depletion for one month. A subset of mice received an OVA/CFA immunization. Sustained CD25+ depletion did not result in anti-HOD autoantibody generation. Further, there was no change in the endogenous frequency of OVA-reactive CD4+ T cells between HOD and B6 mice, regardless of antibody treatment. Similarly, HOD mice treated with depletion (or isotype) antibody and immunized with OVA/CFA did not make detectable anti-HOD autoantibodies. Consistent with lack of detectable autoantibodies, no expansion of OVA-tetramer reactive CD4+ T cells was observed in HOD mice. In contrast, B6 mice (treated with anti-CD25 or isotype antibody) had a detectable expansion of OVA-specific CD4+ T cells as a result of immunization. Conclusions: The data demonstrate a phenotypic difference between the OVA-reactive CD4+ T cells from HOD and B6 mice, with an increase in number of Tregs detectable in HOD mice. Administration of anti-CD25 antibody significantly reduced the number of overall CD25+ cells and Tregs. Prolonged depletion of these cellular subsets did not elicit autoantibodies in HOD mice. Further, immunization of CD25 depleted mice with a strong immune stimulus (OVA/CFA, known to expand OVA-reactive T cells in B6 mice), did not induce anti-HOD autoantibodies nor did it expand OVA-specific autoreactive CD4+ T cells in HOD mice. Together, these data demonstrate that CD25+ cells are not required for the maintenance of RBC-specific T cell tolerance and suggest a role for other regulatory mechanisms. Disclosures No relevant conflicts of interest to declare.

scholarly journals OX40 costimulation and regulatory T cells

Blood ◽  
2007 ◽  
Vol 110 (7) ◽  
pp. 2217-2218
Author(s):  
Jerzy W. Kupiec-Weglinski
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
T Regulatory Cells ◽  
Costimulatory Molecule ◽  
Negative Regulator ◽  
Regulatory Cells ◽  
Activated T Cells

The OX40 T-cell costimulatory molecule, critical for both survival and proliferation of activated T cells, has now been identified as a key negative regulator of Foxp3+ T regulatory cells (Tregs).

scholarly journals CTLA4 blockade expands FoxP3+ regulatory and activated effector CD4+ T cells in a dose-dependent fashion

Blood ◽  
2008 ◽  
Vol 112 (4) ◽  
pp. 1175-1183 ◽  
Author(s):  
Brian Kavanagh ◽  
Shaun O'Brien ◽  
David Lee ◽  
Yafei Hou ◽  
Vivian Weinberg ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Cd4 T Cells ◽  
Cytotoxic T Lymphocyte ◽  
Effector T Cells ◽  
Activated T Cells ◽  
Ctla4 Blockade ◽  
Dose Dependent Fashion ◽  
Dose Dependent

AbstractCytotoxic T lymphocyte–associated antigen 4 (CTLA4) delivers inhibitory signals to activated T cells. CTLA4 is constitutively expressed on regulatory CD4+ T cells (Tregs), but its role in these cells remains unclear. CTLA4 blockade has been shown to induce antitumor immunity. In this study, we examined the effects of anti-CTLA4 antibody on the endogenous CD4+ T cells in cancer patients. We show that CTLA4 blockade induces an increase not only in the number of activated effector CD4+ T cells, but also in the number of CD4+ FoxP3+ Tregs. Although the effects were dose-dependent, CD4+ FoxP3+ regulatory T cells could be expanded at lower antibody doses. In contrast, expansion of effector T cells was seen only at the highest dose level studied. Moreover, these expanded CD4+ FoxP3+ regulatory T cells are induced to proliferate with treatment and possess suppressor function. Our results demonstrate that treatment with anti-CTLA4 antibody does not deplete human CD4+ FoxP3+ Tregs in vivo, but rather may mediate its effects through the activation of effector T cells. Our results also suggest that CTLA4 may inhibit Treg proliferation similar to its role on effector T cells. This study is registered at http://www.clinicaltrials.gov/ct2/show/NCT00064129, registry number NCT00064129.

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