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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Available from: Jeffrey Bluestone, Dec 26, 2013
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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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    • "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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    • "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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