Toll Pathway-Dependent Blockade of CD4+CD25+ T Cell-Mediated Suppression by Dendritic Cells

Yale University, New Haven, Connecticut, United States
Science (Impact Factor: 33.61). 03/2003; 299(5609):1033-6. DOI: 10.1126/science.1078231
Source: PubMed


Toll-like receptors (TLRs) control activation of adaptive immune responses by antigen-presenting cells (APCs). However, initiation of adaptive immune responses is also controlled by regulatory T cells (TR cells), which act to prevent activation of autoreactive T cells. Here we describe a second mechanism of immune induction by TLRs, which is independent of effects on costimulation. Microbial induction of the Toll pathway blocked the suppressive effect of CD4+CD25+ TR cells, allowing activation of pathogen-specific adaptive immune responses. This block of suppressor activity was dependent in part on interleukin-6, which was induced by TLRs upon recognition of microbial products.

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Available from: Chandrashekhar Pasare, Aug 18, 2015
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    • "The nature of the T cell response is profoundly affected by the cytokine milieu in which a T cell is activated but pro-inflammatory cytokines have also the fundamental function to release effector T cells from Treg suppression. In fact, IL-6 produced by DCs after TLR activation have been shown to be fundamental to release effector T cells from regulatory T cells (Treg) suppression (Pasare and Medzhitov, 2003) and persistent TLR stimulation is needed for reversal of Treg mediated tolerance (Yang et al., 2004). TLR8 ligands can also directly stimulate Tregs inhibiting their suppressor activity (Peng et al., 2005). "
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    ABSTRACT: The ability of the immune system to give rise to an effective response against pathogens while maintaining tolerance towards self-tissues has always been an object of keen interest for immunologist. Over the years, different theories have been proposed to explain if and how the immune system is able to discriminate between self and non-self, including the Infectious Non-self theory from Charles Janeway and Polly Matzinger's Danger theory. Nowadays we know Janeway's theory is largely true, however the immune system does respond to injured, stressed and necrotic cells releasing danger signals (DAMPs) with a potent inflammatory response. To avoid unwanted prolonged autoimmune reactions, though, danger-induced inflammation should be tightly regulated. In the present review we discuss how prototypic DAMPs are able to induce inflammation and the peculiarity of danger-induced inflammation, as opposed to a complete immune response to fight pathogen invasions.
    Molecular Immunology 12/2014; 63(2). DOI:10.1016/j.molimm.2014.06.037 · 2.97 Impact Factor
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    • "As discussed above, suppressing DC activity is an effective strategy for preventing the priming of autoreactive T cells in steady-state conditions. However, Treg cell-mediated suppression of DCs is quickly overcome during infection as a result of direct pathogen recognition via various pathogen sensing systems such as TLRs (39, 137), through activation by pro-inflammatory cytokines (138), or by “licensing” of DCs via CD40 stimulation from activated T cells (139). Additionally, pro-inflammatory cytokines made during infection such as IL-1, IL-6, IL-12, and type-1 IFNs can subvert Treg cell function either directly (94, 140), or by rendering effector T cells “resistant” to Treg cell-mediated suppression (58, 141), and this is required to generate appropriate anti-pathogen responses. "
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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 murine models showed that it was expressed in T cells, and upon ligand recognition, the TLR2 complex stimulated antigen-activated T cells (Pasare and Medzhitov, 2003). Stimulation with its ligand has been shown to sustain increased proliferation and survival associated with CD25 expression, enhanced anti-apoptotic protein synthesis, and increased cytotoxic activity of antigen-activated T cells (Cottalorda et al., 2006; Kim et al., 2009; Liu et al., 2006). "
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