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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    • "Recent studies have demonstrated that TLRs can directly or indirectly regulate the suppressive activity of Treg cells[10,15]. In 2003, Chandrashekhar Pasare and Ruslan Medzhitov first demonstrated that LPS, the ligand of TLR4, could interact with TLR4 that was expressed on the surface of DCs and subsequently activated MyD88 signal pathway, thus releasing the suppressive function of Tregs on conventional CD4 + T cells16171819. Pam3Cys-SK4, the ligand of TLR2, could directly function on Tregs, and made the Tregs lose the suppressive function202122. "
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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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    • "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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