Abstract
The mechanisms that underlie the critical dendritic cell (DC) function in maintainance of peripheral immune tolerance are incompletely understood, although the β-catenin signaling pathway is critical for this role. The molecular details by which β-catenin signaling is regulated in DCs are unknown. Mechanical disruption of murine bone marrow-derived DC (BMDC) clusters activates DCs while maintaining their tolerogenic potential and this activation is associated with β-catenin signaling, providing a useful model with which to explore tolerance-associated β-catenin signaling in DCs. In this report, we demonstrate novel molecular features of the signaling events that control DC activation in response to mechanical stimulation. Non-canonical β-catenin signaling is an essential component of this tolerogenic activation and is modulated by adhesion molecules, including integrins. This unique β-catenin-dependent signaling pathway is constitutively active at low levels, suggesting that mechanical stimulation is not necessarily required for induction of this unique activation program. We additionally find that the immunomodulatory cytokine TGF-β antagonizes β-catenin in DCs, thereby selectively suppressing signaling associated with tolerogenic DC activation while having no impact on LPS-induced, β-catenin-independent immunogenic activation. These findings provide new molecular insight into the regulation of a critical signaling pathway for DC function in peripheral immune tolerance.
Highlights
In contrast to significant advances made towards understanding the signals that control dendritic cell (DC) function in activating T cells during inflammation, relatively little is known about the signals that control DC function in suppressing inappropriate T cell responses during steady state [1,2]
Whereas DCs activated by TLR ligands acquire the capacity to stimulate T cell immunity, bone marrow-derived DC (BMDC) activated by cluster disruption have immunophenotypic characteristics of mature DCs, yet functionally resemble naıve DCs in their ability to promote T cell tolerance
It has been proposed that disruption of E-Cadherinmediated cell-cell initiates the tolerogenic program [6], we find that individual BMDCs respond to mechanical stimulation in the absence of cell-cell contacts and that additional adhesion molecules, including integrins, may play an important role in regulating DC activation
Summary
In contrast to significant advances made towards understanding the signals that control dendritic cell (DC) function in activating T cells during inflammation (immunogenic function), relatively little is known about the signals that control DC function in suppressing inappropriate T cell responses during steady state (tolerogenic function) [1,2]. Whereas DCs activated by TLR ligands acquire the capacity to stimulate T cell immunity, BMDCs activated by cluster disruption have immunophenotypic characteristics of mature DCs, yet functionally resemble naıve DCs in their ability to promote T cell tolerance. They stimulate T cells to produce cytokine profiles associated with immune tolerance, and will protect against autoimmune disease when used to immunize recipient mice (6). Activation of DCs in this model (hereafter refered to as tolerogenic activation) is associated with b-catenin signaling that is distinct from signaling pathways commonly associated with DC responses to inflammatory stimuli such as TLR ligands [6]. This model is a useful tool to explore the association between b-catenin signaling and tolerogenic activation, as well as to explore how this critical pathway is regulated in DCs
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