Natural and TGF-β–induced Foxp3+CD4+ CD25+ regulatory T cells are not mirror images of each other

Horwitz, David A.; Zheng, Song Guo; Gray, J. Dixon

doi:10.1016/j.it.2008.06.005

Cited by 288 publications

(257 citation statements)

References 70 publications

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“…Tregs actively suppress immune responses initiated by cells of both the innate and adaptive immune system and have long been considered candidates for the therapeutic treatment of autoimmune and chronic inflammatory diseases. Numerous studies have shown that FOXP3-expressing Tregs can be divided into two distinct subsets: naturally occurring Tregs (nTregs), and peripherally induced Tregs (iTregs), which differentiate under tolerogenic conditions in peripheral lymphoid tissues (4,5). FOXP3-expressing nTregs develop in the thymus via central tolerance mechanisms and, upon egress, they express the naive T cell marker CD45RA until they encounter their cognate Ag and become activated in the periphery (6,7).…”

Section: T Regulatory Cells (Tregs) Play a Critical Role In Establishingmentioning

confidence: 99%

Helios+ and Helios− Cells Coexist within the Natural FOXP3+ T Regulatory Cell Subset in Humans

Himmel

MacDonald

García

et al. 2013

The Journal of Immunology

188

157

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FOXP3-expressing T regulatory cells (Tregs) can be divided into two distinct subsets: naturally occurring Tregs (nTregs) that develop in the thymus, and induced Tregs (iTregs) that differentiate in peripheral tissues upon exposure to Ag in a tolerogenic environment. Recently it has been proposed that expression of Helios, an Ikaros family transcription factor, may specifically identify nTregs, allowing specific tracking of Tregs from different origins in health and disease. Surprisingly, we found that Helios- cells can be readily identified within naive (CD45RA+CD31+CCR7+CD62L+) FOXP3+ Tregs, a finding inconsistent with the notion that lack of Helios expression identifies Ag-experienced iTregs that should express memory markers. To investigate the phenotype and function of naive Helios+ and Helios− Tregs within the nTreg population, we isolated single-cell clones from each subset. We found that both Helios+ and Helios− nTreg clones have a similar suppressive capacity, as well as expression of FOXP3 and cell surface proteins, including CD39 and CTLA-4. Helios− nTregs, however, produced significantly more CCL3 and IFN-γ compared with Helios+ nTregs. Despite increased cytokine/chemokine production, Helios− FOXP3+ nTreg clones were demethylated at the FOXP3 Treg-specific demethylated region, indicative of Treg lineage stability. When cultured under Th1-polarizing conditions, Helios+ and Helios− nTreg clones had an equal ability to produce IFN-γ. Collectively, these data show that a lack of Helios expression does not exclusively identify human iTregs, and, to our knowledge, the data provide the first evidence for the coexistence of Helios+ and Helios− nTregs in human peripheral blood.

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Section: T Regulatory Cells (Tregs) Play a Critical Role In Establishingmentioning

confidence: 99%

Helios+ and Helios− Cells Coexist within the Natural FOXP3+ T Regulatory Cell Subset in Humans

Himmel

MacDonald

García

et al. 2013

The Journal of Immunology

188

157

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“…8 The comparison of the similarities and differences between nTreg and iTreg cells has been previously reviewed. 3,9,10 Foxp3 1 iTreg cells can be induced ex vivo by TGF-b or IL-10. 11,12 Although many factors may promote the differentiation and development of iTreg cells, TGF-b and its receptor signaling pathway is critical because Foxp3 1 iTreg cells cannot be induced without a TGF-b signal.…”

Section: Introductionmentioning

confidence: 99%

The role of all-trans retinoic acid in the biology of Foxp3+ regulatory T cells

Liu

Wang

et al. 2015

Cell Mol Immunol

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Regulatory T (Treg) cells are necessary for immune system homeostasis and the prevention of autoimmune diseases. Foxp3 is specifically expressed in Treg cells and plays a key role in their differentiation and function. Foxp3 1 Treg cells are consisted of naturally occurring, thymus-derived Treg (nTreg) and peripheral-induced Treg (iTreg) cells that may have different functional characteristics or synergistic roles. All-trans retinoic acid (atRA), a vitamin A metabolite, regulates a wide range of biological processes, including cell differentiation and proliferation. Recent studies demonstrated that atRA also regulates the differentiation of T helper (Th) cells and Treg cells. Moreover, atRA also sustains nTreg stability under inflammatory conditions. In this review, we summarize the significant progress of our understanding of the role(s) and mechanisms of atRA in Treg biology.

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“…2014. 44: 1143-1155 inducible Treg (iTreg) cells generated in the periphery from naïve T cells [10,11]. It is speculated that nTreg and iTreg cells play distinct roles in controlling adaptive immunity [12].…”

mentioning

confidence: 99%

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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Natural and TGF-β–induced Foxp3+CD4+ CD25+ regulatory T cells are not mirror images of each other

Cited by 288 publications

References 70 publications

Helios+ and Helios− Cells Coexist within the Natural FOXP3+ T Regulatory Cell Subset in Humans

Helios+ and Helios− Cells Coexist within the Natural FOXP3+ T Regulatory Cell Subset in Humans

The role of all-trans retinoic acid in the biology of Foxp3+ regulatory T cells

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

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