CD25+CD4+ regulatory T cells exert in vitro suppressive activity independent of CTLA-4

Kataoka, Hiroshi; Takahashi, Shingo; Takase, Kan; Yamasaki, Satoshi; Yokosuka, Tadashi; Koike, Takao; Saito, Takashi

doi:10.1093/intimm/dxh221

Cited by 67 publications

(58 citation statements)

References 31 publications

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“…3D). These results are consistent with a previous study performed on CTLA-4 transgenic regulatory cells (30). Previous studies have also shown that regulatory cells from CTLA-4-deficient mice retain regulatory activity (30 -32).…”

Section: Effect Of Ctla-4 Overexpression On Regulatory T Cellssupporting

confidence: 93%

CTLA-4 Overexpression Inhibits T Cell Responses through a CD28-B7-Dependent Mechanism

Engelhardt

Sullivan

Allison³

2006

The Journal of Immunology

117

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CTLA-4 has been shown to be an important negative regulator of T cell activation. To better understand its inhibitory action, we constructed CTLA-4 transgenic mice that display constitutive cell surface expression of CTLA-4 on CD4 and CD8 T cells. In both in vivo and in vitro T cell responses, CTLA-4 overexpression inhibits T cell activation. This inhibition is dependent on B7 and CD28, suggesting that overexpressed CTLA-4 inhibits responses by competing with CD28 for B7 binding or by interfering with CD28 signaling. In addition, expression of the transgene decreases the number of CD25+Foxp3+ T cells in these mice, but does not affect their suppressive ability. Our data confirm the activity of CTLA-4 as a negative regulator of T cell activation and that its action may be by multiple mechanisms.

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Section: Effect Of Ctla-4 Overexpression On Regulatory T Cellssupporting

confidence: 93%

CTLA-4 Overexpression Inhibits T Cell Responses through a CD28-B7-Dependent Mechanism

Engelhardt

Sullivan

Allison³

2006

The Journal of Immunology

117

View full text Add to dashboard Cite

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“…Some reports argue that anti-CTLA-4 treatment is likely to influence the action of Treg, but more recent data imply that the antitumor effects of CTLA-4 blockade are due to increased T cell activation rather than inhibition of Treg. 42,43 In our model, detailed analysis showed that CTLA-4 blockade and CD25 depletion markedly enhanced the frequency of glioma-specific effector T cells with a predominant increase in the CD81 T cell numbers. This is in line with previous observations that the frequencies of antigenspecific CD81 T cells are increased most prominently if CTLA-4 blockade is performed in CD25-depleted animals.…”

Section: Discussionmentioning

confidence: 75%

CD4+FoxP3+ regulatory T cells gradually accumulate in gliomas during tumor growth and efficiently suppress antiglioma immune responses in vivo

Grauer

Nierkens

Bennink

et al. 2007

Intl Journal of Cancer

202

165

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The suppressive activity of regulatory T cells (Treg) has been implicated as an important factor limiting immune mediated destruction of tumor cells. However, not much is known about the presence and function of Treg within tumors. Here we show in a syngeneic murine glioma model a time-dependent accumulation of CD41FoxP31 Treg in brain tumors. Further analysis revealed a time-dependent upregulation of CD25, CTLA-4, GITR and CXCR4 on intratumoral CD41FoxP31 Treg during tumor growth. Moreover, freshly isolated intratumoral Treg were highly suppressive when tested directly ex vivo. Treatment with anti-CD25 monoclonal antibodies (mAbs) significantly reduced the number of these highly suppressive CD41FoxP31 cells within the growing tumor and provoked a CD4 and CD8 T cell dependent destruction of the glioma cells. Combining Treg depletion with administration of blocking CTLA-4 mAbs further boosted gliomaspecific CD41 and CD81 effector T cells as well as antiglioma IgG2a antibody titers resulting in complete tumor eradication without any signs of autoimmunity. These data illustrate that intratumoral accumulation and activation of CD41FoxP31 Treg act as a dominant immune escape mechanism for gliomas and underline the importance of controlling tumor-infiltrating Treg in glioma immunotherapy. ' 2007 Wiley-Liss, Inc. Key words: glioma; regulatory T cell; immune escapeThe naturally occurring CD41 regulatory T cells (Treg) are continuously produced by the thymus and gradually settled in secondary lymphoid organs. They constitute 5-15% of the overall CD41 T cell population and exert a strong suppressive activity on multiple components of the immune system. Although their repertoire in antigen recognition is quite diverse, they preferentially recognize tissue specific self-antigens. As many tumors express self-antigens, CD41 Treg do not only dominantly suppress the activation and expansion of different effector cells capable of mediating autoimmunity, but also effective antitumor responses. 1 So far the most specific marker for naturally occurring CD41 Treg, at least in mice, is FoxP3, a member of the forkhead family of DNA-binding transcription factors. FoxP3 is highly expressed in naturally occurring CD41 Treg and clearly linked to their suppressive function. [2][3][4] Other molecules that are constitutively expressed on CD41 Treg are the IL-2 receptor a-chain (CD25), cytotoxic lymphocyte-associated antigen-4 (CTLA-4) and different members of the tumor necrosis factor (TNF) receptor superfamily like the glucocorticoid-induced TNF related protein (GITR). These molecules, however, do not uniquely distinguish the CD41 Treg from conventional CD41 T cells that can temporally upregulate these molecules following activation. [5][6][7][8][9] Recent data also suggest an important role of Toll-like receptors (TLRs) in controlling Treg. 10 TLR2-triggering on murine Treg in combination with T cell receptor ligation resulted, both in vitro and in vivo, in proliferation of the otherwise anergic Treg. Moreover, the suppressive phenotype o...

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“…This finding further extends the report by DiPaolo et al [28], and suggests that control of CD80/86 expression on DCs is critical for the suppressive effects of iTreg cells. This observation is important as iTreg cell-mediated resistance of DCs to LPSinduced maturation could play a role in adjusting the intensity of antimicrobial immune responses and sustaining gastrointestinal homeostasis [29,30].The role of CTLA4 in Treg cell-mediated immune suppression remains elusive [31,32]. Our studies indicate that CTLA4 expression on iTreg cells is important for iTreg-cell function as blocking this molecule completely abolished the capacity of iTreg cells to regulate DC maturation status.…”

mentioning

confidence: 78%

Cell‐extrinsic CTLA4‐mediated regulation of dendritic cell maturation depends on STAT3

2014

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Regulatory T (Treg) cells suppress immune responses by downregulating the expression of costimulatory molecules CD80 and CD86 on dendritic cells (DCs) through cytotoxic T lymphocyte antigen 4 (CTLA4). However, it is unclear whether inducible Treg (iTreg) cellscan hamper immune responses via the same mechanism. Moreover, whether a reverse signal sent by CTLA4 alone is sufficient to prevent maturation of DCs has never been evaluated. Here, we demonstrate that stimulation of DCs with CTLA4, either expressed by inducible Treg cells or by cross-linking with CTLA4Fc fusion protein, can significantly inhibit LPS-induced CD80 and CD86 mRNA and protein expression in both mouse and human DCs. Importantly, CTLA4Fc-treated DCs had reduced ability to stimulate CD4 + and CD8 + T-cell proliferation and cytokine production in both syngeneic and allogeneic settings. We also investigated the molecular mechanism involved in the induction of tolerogenic DCs by CTLA4. We determined that the interaction of CTLA4 with its high affinity ligand CD80 on DCs induces STAT3 phosphorylation followed by reduction of NF-κB activity, leading to suppression of CD80 and CD86 gene transcription and protein production. Our work opens new windows for the generation of tolerogenic DCs that could ultimately be used for treating autoimmune diseases and transplant rejection. Keywords: Dendritic cells r Immune regulation r Regulatory T cells r ToleranceAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionDendritic cells (DCs) play a central role in the initiation and regulation of immune responses [1]. Although traditionally viewed as immunity inducers, in the absence of inflammatory danger signals, DCs participate in the maintenance of peripheral tolerance [2] and can induce T-cell deletion, anergy and generation and expansion of regulatory T (Treg) cells [3]. These tolerogenic DCs show decreased expression of costimulatory molecules such as CD80Correspondence: Dr. Li Zhang e-mail: lzhang@uhnres.utoronto.ca and CD86 and reduced production of proinflammatory cytokines [4]. Several in vitro methods have been developed in order to generate tolerogenic DCs [5]. Additionally, a growing body of experimental data highlights the role of Treg cells in maintaining tolerance through the suppression of DC immunostimulatory capacity [6][7][8][9]. However, the molecular mechanisms by which Treg cells modulate DC function remain obscure. Elucidation of the mechanisms governing DC maturation may facilitate their use in treating a variety of immune-related conditions including autoimmune diseases and transplantation.CD4 + CD25 + Foxp3 + Treg cells play a pivotal role in maintaining self-tolerance and preventing autoimmunity. At least two major subtypes of CD4 + CD25 + Foxp3 + Treg cells have been identified: Thymus-derived natural T regulatory (nTreg) cells and C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu1144 Aleksandra Kowalczyk et al. Eur. J. Immunol. 2014. 44: 1143-1155 ...

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CD25+CD4+ regulatory T cells exert in vitro suppressive activity independent of CTLA-4

Cited by 67 publications

References 31 publications

CTLA-4 Overexpression Inhibits T Cell Responses through a CD28-B7-Dependent Mechanism

CTLA-4 Overexpression Inhibits T Cell Responses through a CD28-B7-Dependent Mechanism

CD4+FoxP3+ regulatory T cells gradually accumulate in gliomas during tumor growth and efficiently suppress antiglioma immune responses in vivo

Cell‐extrinsic CTLA4‐mediated regulation of dendritic cell maturation depends on STAT3

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