TGF-β1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells

Marie, Julien C.; Letterio, John J.; Gavin, Marc A.; Rudensky, Alexander Y.

doi:10.1084/jem.20042276

Cited by 903 publications

(712 citation statements)

References 31 publications

(47 reference statements)

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“…Furthermore, the above studies did not examine the possibility that cell surface TGF-b1, from autocrine or paracrine sources, mediates its effects by actively signaling in CD4 + CD25 + Treg cells themselves, possibly maintaining their survival, differentiation, expansion, or suppressive effector mechanism, as suggested by recent reports [22,31]. In this regard, a recent study by Marie et al has shown that TGF-b1 signaling in Treg cells may promote Foxp3 expression and subsequent Treg function [34]. Thus, it is possible that the very slight increase in intestinal inflammation observed in groups receiving TGF-b1 -/-compared to WT Treg cells is not exclusively due to contaminating effector T cells, but instead result at least in part from a lack of TGF-b1 signaling in Treg cells and consequential fading of CD4 + CD25 + Treg cell function over time.…”

Section: Discussionmentioning

confidence: 95%

TGF‐β1 production by CD4⁺CD25⁺ regulatory T cells is not essential for suppression of intestinal inflammation

et al. 2005

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Naturally occurring CD4 + CD25 + regulatory T cells (Treg) are potent suppressors of CD4 + and CD8 + T cell responses in vitro and inhibit several organ-specific autoimmune diseases. While most in vitro studies suggest that CD4 + CD25 + Treg cells adopt a cytokine-independent but cell contact-dependent mode of T cell regulation, their precise mechanism of suppression in vivo remains largely unknown. Here we examine the functional contribution of Treg cell-derived TGF-b1 and effector T cell responsiveness to TGF-b in CD4 + CD25 + T cell-mediated suppression of inflammatory bowel disease (IBD). We show that CD4 + CD25 + Treg cells from either TGF-b1 +/+ or neonatal TGF-b1 -/-mice can suppress the incidence and severity of IBD as well as colonic IFN-c mRNA expression induced by WT CD4 + CD25 -effector T cells. Furthermore, TGF-b-resistant Smad3 -/-CD4 + CD25 + Treg cells are equivalent to WT Treg cells in their capacity to suppress disease induced by either WT or Smad3 -/-CD4 + CD25 -effector T cells. Finally, anti-TGF-b treatment exacerbates the colitogenic potential of CD4 + CD25 -effector T cells in the absence of CD4 + CD25 + Treg cells.Together, these data demonstrate that in certain situations CD4 + CD25 + T cells are able to suppress intestinal inflammation by a mechanism not requiring Treg cell-derived TGF-b1 or effector T cell/Treg cell responsiveness to TGF-b via Smad3. IntroductionCD25 (IL-2Ra chain)-expressing CD4 + T cells, which constitute 5-10% of normal CD4 + T cells, play a critical role in the induction and maintenance of peripheral tolerance [1,2]. These naturally occurring CD4 + CD25 + regulatory T (Treg) cells consist of an anergic lymphocyte population with potent immunosuppressive functions in vivo, as the depletion of CD25-expressing CD4 + T cells correlates with increased immunity to tumors, grafts and intracellular pathogens and provokes the induction of multiple inflammatory diseases including autoimmmune gastritis (AIG) and inflammatory bowel disease (IBD) [3,4]. Currently, the mechanism(s) by which CD4 + CD25 + Treg cells mediate suppression in vitro and in vivo is unclear. Following TCR activation, CD4 + CD25 + Treg cells suppress the in vitro proliferation and cytokine production of CD4 + and CD8 + T cells in an antigen nonspecific, but contact-dependent manner that does not appear to involve modulation of APC function [5][6][7]. The role of regulatory cytokines in CD4 + CD25 + Treg cell control of inflammation in vivo appears to be tissue and/ or context-dependent. While CD4 + CD25 + Treg cells from IL-4 -/-and IL-10 -/-mice are as effective as WT CD4 + CD25 + T cells in mediating suppression of AIG, CD4 + CD25 + Treg cells from IL-10 -/-mice cannot control IBD induced by antigen-experienced effector T cells [8,9]. Similarly, IL-10 -/-CD4 + CD25 + Treg cells, in contrast to WT cells, fail to attenuate effector T cell responses to Leishmania major in resistant C57BL/6 mice [10].TGF-b1 is a potently suppressive cytokine that plays a critical role in the regulation of immune function, a...

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Section: Discussionmentioning

confidence: 95%

TGF‐β1 production by CD4⁺CD25⁺ regulatory T cells is not essential for suppression of intestinal inflammation

et al. 2005

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“…In this study, we observed that UC MSCT could markedly up-regulate the percentage of CD4ϩFoxP3ϩ Treg cells in peripheral blood mononuclear cells 3 months after transplantation, and the percentage continued to increase after 6 months. In addition, the restoration of Treg cells was associated with a concomitant increase in TGF␤ and, to a lesser degree, an increase in IL-10, 2 cytokines that play important roles in Treg cell activation and function (35,36). Augmentation of the Treg cell pathway may be one of the mechanisms underlying the therapeutic effect of UC MSCs.…”

Section: Discussionmentioning

confidence: 99%

Umbilical cord mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus

Sun

Wang

Liang

et al. 2010

Arthritis & Rheumatism

413

305

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Objective. Umbilical cord (UC)-derived mesenchymal stem cells (MSCs) have shown marked therapeutic effects in a number of diseases in animal studies, based on their potential for self-renewal and differentiation. No data are available on the effectiveness of UC MSC transplantation (MSCT) in human autoimmune disease. This study was undertaken to assess the efficacy and safety of allogeneic UC MSCT in patients with severe and treatment-refractory systemic lupus erythematosus (SLE).Methods. We conducted a single-arm trial that involved 16 SLE patients whose disease was refractory to standard treatment or who had life-threatening visceral involvement. All of the patients gave consent and underwent UC MSCT. Clinical changes were evaluated before and after transplantation using the SLE Disease Activity Index (SLEDAI), measurement of serum antinuclear antibody (ANA), anti-double-stranded DNA (anti-dsDNA) antibody, serum complement C3 and C4, and albumin levels, and assessment of and renal function. Evaluation of potential mechanisms of MSCT effects focused on the percentage of peripheral blood Treg cells and serum levels of cytokines.Results. From April 2007 to July 2009, a total of 16 patients with active SLE were enrolled and underwent UC MSCT. The median followup time after MSCT was 8.25 months (range 3-28 months). Significant improvements in the SLEDAI score, levels of serum ANA, anti-dsDNA antibody, serum albumin, and complement C3, and renal function were observed. Clinical remission was accompanied by an increase in peripheral Treg cells and a re-established balance between Th1-and Th2-related cytokines. Significant reduction in disease activity was achieved in all patients, and there has been no recurrence to date and no treatment-related deaths.Conclusion. Our findings indicate that UC MSCT results in amelioration of disease activity, serologic changes, and stabilization of proinflammatory cytokines. These data provide a foundation for conducting a randomized controlled trial of this new therapy for severe and treatment-refractory SLE.Systemic lupus erythematosus (SLE) is an inflammatory disease with protean manifestations, ranging from relatively minor skin and joint symptoms to severe life-threatening major organ involvement, such as nephritis and neuropsychiatric complications (1). It is characterized by the presence of autoreactive T and B lymphocytes, with polyclonal activation of B cells and the consequent production of autoantibodies by plasma ClinicalTrials.gov identifier: NCT00698191.

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Section: Introductionmentioning

confidence: 99%

“…IL-2 and IL-2R knockout mice have few, if any, nTreg and develop severe lymphoproliferation and autoimmunity [13,14]. TGF-b1 or IL-10 have been shown to expand Treg and even convert CD4 1 CD25 À T cells into CD4 1 CD25 1 T cells with suppressive functions [13,[15][16][17][18].Antigen presenting cells (APC) express both MHC class II as well as B7 molecules and secrete cytokines that may modulate the differentiation of T cells into either T-effector or T-regulatory cells [19]. Most studies have focused on dendritic cells (DC), which are thought to be key players in generating peripheral Treg [20][21][22].…”

mentioning

confidence: 99%

Resting B cells expand a CD4⁺CD25⁺Foxp3⁺ Treg population via TGF‐β3

Shah

Qiao

2008

Eur J Immunol

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Regulatory T cells (Treg) play critical roles in maintaining tolerance and preventing autoimmunity. It is not fully clear how these cells are generated and maintained. Here, we show that resting B cells are able to expand Treg. This expansion requires TGF-b3 and signaling through the TCR and CD28. Upon activation, B cells express less TGF-b3, which reduces their capacity to expand Treg and which also results in increased Treg death. This may ensure that B cells can function as potent professional antigen presenting cells during infections. However, in the absence of any infection, we find that B-cell-deficient lMT mice have decreased percentages of Treg in the periphery. Our data suggest that resting B cells, which may be presenting self-antigens to T cells, can expand and maintain specific Treg and thus might be involved in the prevention of autoimmunity. Key words: B cells . Regulatory T cells . Tolerance Supporting Information available online IntroductionRegulatory T cells (Treg) are a subset of T cells that can actively suppress innate as well as adaptive immunity and have been implicated in self-tolerance, autoimmunity, cancer, transplantation immunology and a myriad of infectious diseases [1][2][3][4][5][6]. There are numerous different subsets of Treg based on their phenotypic markers, amonge which the naturally occurring Treg (nTreg) population is well studied and characterized. nTreg are a subset of CD4 1 T cells expressing CD25 and the transcription factor Forkhead box protein 3 (Foxp3). Foxp3 has been shown to be the master regulator for the generation of nTreg. Although Foxp3 À/À mice lack CD4 1 CD25 1 T cells, expression of Foxp3 in CD4 1 CD25 -T cells is sufficient for converting them into CD4 1 CD25 1 T cells with suppressive function [7,8].CD4 1 CD25 1 Foxp3 1 Treg arise in the thymus and enter into the periphery where they constitute $5-10% of the CD4 1 T cells. nTreg generation in the thymus is thought to require high-affinity peptide-MHC class II interactions in contrast to low-affinity peptide-MHC class II interactions required for positive selection of conventional CD4 1 T cells [9,10]. There are also strong evidences for the generation of CD4 1 CD25 1 Foxp3 1 Treg in the periphery. Experiments carried out in thymectomized or RAG-2-deficient mice lacking CD4 1 CD25 1 T cells show that nTreg can be generated in the periphery from CD4 1 CD25 À T cells [11,12].In addition to co-stimulation via the B7-CD28 and TCR-MHC class II pathways, various cytokines such as IL-2, TGF-b1 and IL-10 have been associated with the generation of peripheral Treg. IL-2 and IL-2R knockout mice have few, if any, nTreg and develop severe lymphoproliferation and autoimmunity [13,14]. TGF-b1 or IL-10 have been shown to expand Treg and even convert CD4 1 CD25 À T cells into CD4 1 CD25 1 T cells with suppressive functions [13,[15][16][17][18].Antigen presenting cells (APC) express both MHC class II as well as B7 molecules and secrete cytokines that may modulate the differentiation of T cells into either T-effector or T-r...

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TGF-β1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells

Cited by 903 publications

References 31 publications

TGF‐β1 production by CD4⁺CD25⁺ regulatory T cells is not essential for suppression of intestinal inflammation

TGF‐β1 production by CD4⁺CD25⁺ regulatory T cells is not essential for suppression of intestinal inflammation

Umbilical cord mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus

Resting B cells expand a CD4⁺CD25⁺Foxp3⁺ Treg population via TGF‐β3

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TGF-β1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells

Cited by 903 publications

References 31 publications

TGF‐β1 production by CD4+CD25+ regulatory T cells is not essential for suppression of intestinal inflammation

TGF‐β1 production by CD4+CD25+ regulatory T cells is not essential for suppression of intestinal inflammation

Umbilical cord mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus

Resting B cells expand a CD4+CD25+Foxp3+ Treg population via TGF‐β3

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TGF‐β1 production by CD4⁺CD25⁺ regulatory T cells is not essential for suppression of intestinal inflammation

TGF‐β1 production by CD4⁺CD25⁺ regulatory T cells is not essential for suppression of intestinal inflammation

Resting B cells expand a CD4⁺CD25⁺Foxp3⁺ Treg population via TGF‐β3