Although it has been proposed that disruption of E-Cadherinmediated cell-cell initiates the tolerogenic Clozapine N-oxide program, 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. We further demonstrate that activated b-catenin is not only sufficient to promote BMDC maturation, it is indeed a necessary component for tolerogenic DC activation by mechanical stimulation. By contrast, LPS-induced immunogenic maturation is independent of b-catenin. Finally, we demonstrate that TGF-b disrupts b-catenin signaling, thereby selectively suppressing this response while leaving immunogenic activation undisturbed. b-catenin signaling is constitutively active in tolerogenic DC subsets in vivo, yet the signal that initiates b-catenin signaling in steady state DCs is unknown. Although peripheral tissues like the skin are subject to mechanical agitation, evidence has been lacking as to whether such stimulation may itself be required for steady state DC function. Wnt ligands are expressed by DCs in vivo suggesting the possibility of autocrine activation in the absence of external signals. Therefore, it is noteworthy that in the BMDC model, b-catenin-dependent maturation will occur spontaneously in the absence of any exogenous stimulus. We find, however, that adhesive interactions between DCs and the tissue culture surface modulate the extent of spontaneous maturation, indicating that non-canonical signals contribute to the regulation of the b-catenin pathway in DCs. Based on our interpretation of the in vitro model, we propose that b-catenin-depdendent tolerogenic DC Deltamethrin function in vivo may not be driven by mechanical stimulation per se, but rather by a constitutively or stochastically active signal modulated by adhesion molecules and intensified by mechanical stimulation. Further studies will be required to determine the contributions of canonical wnt signaling and alternative signaling mediated by adhesion molecules to steady state tolerogenic DC function in vivo. Our data provide insight into mechanisms that may regulate signaling pathways associated with tolerogenic DC function in vivo. TGF-b is a well-established regulator of DC development, chemoattraction and function, particularly for DC subsets in peripheral tissues such as skin, the lungs, and the gut. As TGF-b is strongly associated with immune suppression, it is perhaps counterintuitive that TGF��b antagonizes a signaling pathway associated with tolerogenic DC function.