Tang Q, Adams JY, Tooley AJ, Bi M, Fife BT, Serra P et al.. Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice. Nat Immunol 7: 83-92

Department of Microbiology, Immunology and Infectious Diseases, The University of Calgary, Calgary, Alberta, Canada
Nature Immunology (Impact Factor: 20). 02/2006; 7(1):83-92. DOI: 10.1038/ni1289
Source: PubMed


The in vivo mechanism of regulatory T cell (T(reg) cell) function in controlling autoimmunity remains controversial. Here we have used two-photon laser-scanning microscopy to analyze lymph node priming of diabetogenic T cells and to delineate the mechanisms of T(reg) cell control of autoimmunity in vivo. Islet antigen-specific CD4(+)CD25(-) T helper cells (T(H) cells) and T(reg) cells swarmed and arrested in the presence of autoantigens. These T(H) cell activities were progressively inhibited in the presence of increasing numbers of T(reg) cells. There were no detectable stable associations between T(reg) and T(H) cells during active suppression. In contrast, T(reg) cells directly interacted with dendritic cells bearing islet antigen. Such persistent T(reg) cell-dendritic cell contacts preceded the inhibition of T(H) cell activation by dendritic cells, supporting the idea that dendritic cells are central to T(reg) cell function in vivo.

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    • "Indeed, one key mechanism by which Treg cells blunt T cell responses is by regulating DC abundance (124, 125), and by maintaining DCs in a less stimulatory state by CTLA-4-mediated stripping of the co-stimulatory ligands, CD80 and CD86 (123, 126). Analysis of Treg cell behavior in secondary lymphoid tissues showed that they serially interact with DCs, and that this in turn inhibited stable contacts between DCs and naïve CD4+ T cells, preventing their activation and priming (127, 128). It is therefore intriguing to speculate that Treg production of IL-10 is a major mechanism by which these cells regulate inflammation at environmental interfaces, whereas CTLA-4-dependent regulation of DC function is a regulatory mechanism that predominates in secondary lymphoid tissues where it controls the initial activation and expansion of naïve autoreactive T cells. "
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    ABSTRACT: Foxp3(+) regulatory T cells (Treg cells) are essential for establishing and maintaining self-tolerance, and also inhibit immune responses to innocuous environmental antigens. Imbalances and dysfunction in Treg cells lead to a variety of immune-mediated diseases, as deficits in Treg cell function contribute to the development autoimmune disease and pathological tissue damage, whereas overabundance of Treg cells can promote chronic infection and tumorigenesis. Recent studies have highlighted the fact that Treg cells themselves are a diverse collection of phenotypically and functionally specialized populations, with distinct developmental origins, antigen-specificities, tissue-tropisms, and homeostatic requirements. The signals directing the differentiation of these populations, their specificities and the mechanisms by which they combine to promote organ-specific and systemic tolerance, and how they embody the emerging property of regulatory memory are the focus of this review.
    Frontiers in Immunology 07/2014; 5:333. DOI:10.3389/fimmu.2014.00333
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    • "In the absence of infection or inflammation, antigen presentation by steady-state dendritic cells (DC) leads to T cell tolerance where T cells are driven to apoptosis or rendered unresponsive, and this is an important mechanism preventing progression to autoimmune diseases [1], [2]. In addition to APC-mediated control of naive T-cell differentiation, CD4+CD25+FoxP3+ regulatory T cells (Treg) prevent overexuberant T-cell responses by limiting T-cell activation and differentiation in lymphoid tissues and effector function at target sites [3], [4]. Treg also participate in immune regulation and tolerance through mechanisms that include promoting Treg differentiation from naive CD4+ T cells [5] and modulating DC phenotype and function [6]–[8]. "
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    ABSTRACT: Absorption of IL-2 is one proposed mechanism of CD4+CD25+FoxP3+ regulatory T cell (Treg) suppression. Direct in vivo experimental evidence for this has recently been obtained. While modulation of IL-2 bioavailability controls CD8+ T-cell effector differentiation under strongly immunogenic conditions it is not known whether Treg modulate CD8+ T cell responses through this mechanism under steady-state conditions. Here we assess this using a mouse model in which dendritic cells (DC) are manipulated to present cognate antigen to CD8+ T cells either in the steady-state or after activation. Our observations show that Treg exert a check on expansion and effector differentiation of CD8+ T cells under strongly immunogenic conditions associated with TLR ligand activation of DC, and this is mediated by limiting IL-2 availability. In contrast, when DC remain unactivated, depletion of Treg has little apparent effect on effector differentiation or IL-2 homeostasis. We conclude that while modulation of IL-2 homeostasis is an important mechanism through which Treg control CD8+ effector differentiation under immunogenic conditions, this mechanism plays little role in modulating CD8+ T-cell differentiation under steady-state conditions.
    PLoS ONE 01/2014; 9(1):e85455. DOI:10.1371/journal.pone.0085455 · 3.23 Impact Factor
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    • "However, suppressive cytokine release of IL-10 (Roncarolo et al., 2006), TGF-b (Coffman et al., 2009), and IL-35 (Collison et al., 2007), as well as IL-2 depletion (Thornton & Shevach, 1998; Pandiyan et al., 2007), have been shown to mediate suppression of Teffs without direct contact. Further, Tregs are known to suppress proliferation by interacting with APCs, interfering with costimulatory signals (Cederbom et al., 2000; Misra et al., 2004; Tang et al., 2006) or depleting metabolites (Fallarino et al., 2003; Yan et al., 2010). We have investigated several mechanisms of Treg-mediated suppression within the context of aging. "
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    ABSTRACT: Regulatory T cell (Treg, CD4+ CD25+) dysfunction is suspected to play a key role in immune senescence and contributes to increased susceptibility to diseases with age by suppressing T cell responses. FoxP3 is a master regulator of Treg function and its expression is under control of several epigenetically labile promoters and enhancers. Demethylation of CpG sites within these regions is associated with increased FoxP3 expression and development of a suppressive phenotype. We examined differences in FoxP3 expression between young (3-4 months) and aged (18-20 months) C57BL/6 mice. DNA from CD4+ T cells is hypomethylated in aged mice, which also exhibit increased Treg numbers and FoxP3 expression. Additionally, Treg from aged mice also have greater ability to suppress effector T cell (Teff) proliferation in vitro than Tregs from young mice. Tregs from aged mice exhibit greater redox remodeling-mediated suppression of Teff proliferation during co-culture with DCs by decreasing extracellular cysteine availability to a greater extent than Tregs from young mice, creating an adverse environment for Teff proliferation. Tregs from aged mice produce higher IL-10 levels and suppress CD86 expression on DCs more strongly than Tregs from young mice, suggesting decreased T cell activity. Taken together, these results reveal a potential mechanism of higher Treg-mediated activity that may contribute to increased immune suppression with age. This article is protected by copyright. All rights reserved.
    Aging cell 12/2013; 13(3). DOI:10.1111/acel.12191 · 6.34 Impact Factor
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