Abstract
ABSTRACTThe signaling pathways activated following interaction between dendritic cells (DCs) and a pathogen determine the polarization of effector T-cell and regulatory T-cell (Treg) responses to the infection. Several recent studies, mostly in the context of bacterial infections, have shown that the Wnt/β-catenin pathway plays a major role in imparting tolerogenic features in DCs and in promotion of Treg responses. However, the significance of the Wnt/β-catenin pathway’s involvement in regulating the immune response to the fungal species is not known. Using Aspergillus fumigatus, a ubiquitous airborne opportunistic fungal species, we show here that fungi activate the Wnt/β-catenin pathway in human DCs and are critical for mediating the immunosuppressive Treg responses. Pharmacological inhibition of this pathway in DCs led to inhibition of maturation-associated molecules and interleukin 10 (IL-10) secretion without affecting the majority of the inflammatory cytokines. Furthermore, blockade of Wnt signaling in DCs suppressed DC-mediated Treg responses in CD4+ T cells and downregulated both tumor necrosis factor alpha (TNF-α) and IL-10 responses in CD8+ T cells. Mechanistically, induction of β-catenin pathway by A. fumigatus required C-type lectin receptors and promoted Treg polarization via the induction of programmed death-ligand 1 on DCs. Further investigation on the identity of fungal molecular patterns has revealed that the cell wall polysaccharides β-(1, 3)-glucan and α-(1, 3)-glucan, but not chitin, possess the capacity to activate the β-catenin pathway. Our data suggest that the Wnt/β-catenin pathway is a potential therapeutic target to selectively suppress the Treg response and to sustain the protective Th1 response in the context of invasive aspergillosis caused by A. fumigatus.
Highlights
The signaling pathways activated following interaction between dendritic cells (DCs) and a pathogen determine the polarization of effector T-cell and regulatory T-cell (Treg) responses to the infection
To understand the role of the Wnt/b-catenin pathway during A. fumigatus infection, we first assessed the status of this pathway by immunoblot-based evaluation of the levels of active b-catenin and p-glycogen synthase kinase-3 beta (GSK-3b) in DCs upon stimulation with swollen conidia
Human monocyte-derived DCs stimulated with paraformaldehyde-inactivated A. fumigatus swollen conidia for 24 h showed increased levels of active b-catenin and p-GSK-3b, indicating the activation of the Wnt/b-catenin pathway (Fig. 1A)
Summary
The signaling pathways activated following interaction between dendritic cells (DCs) and a pathogen determine the polarization of effector T-cell and regulatory T-cell (Treg) responses to the infection. Using Aspergillus fumigatus, a ubiquitous airborne opportunistic fungal species, we show here that fungi activate the Wnt/b-catenin pathway in human DCs and are critical for mediating the immunosuppressive Treg responses Pharmacological inhibition of this pathway in DCs led to inhibition of maturation-associated molecules and interleukin 10 (IL-10) secretion without affecting the majority of the inflammatory cytokines. During pathogen-DC interaction, the signaling pathways activated and cytokines secreted by DCs play a vital role in deciding T-cell responses to the infection In this regard, recent studies have demonstrated the involvement of Wnt/b-catenin pathway for the induction of tolerogenic functions in DCs and promotion of Treg responses via various anti-inflammatory mechanisms, like expression of IL-10, transforming growth factor beta (TGF-b), and retinoic acid [20,21,22,23,24]. The nonphosphorylated active form of b-catenin accumulates in the cytoplasm and subsequently translocates to the nucleus, where it acts as a transcription cofactor to control the expression of various genes by interacting with T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) [25, 26]
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