Wnt-b-Catenin Signaling in Human Dendritic Cells Mediates Regulatory T-Cell Responses to Fungi via the PD-L1 Pathway

Anupama Karnam, Srinivasa Reddy Bonam, Naresh Rambabu, Sarah Sze Wah Wong, Vishukumar Aimanianda, Jagadeesh Bayry

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

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. Several recent studies, mostly in the context of bacterial infections, have shown that the Wnt/b-catenin pathway plays a major role in imparting tolerogenic features in DCs and in promotion of Treg responses. However, the significance of the Wnt/b-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/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. Furthermore, blockade of Wnt signaling in DCs suppressed DC-mediated Treg responses in CD41 T cells and downregulated both tumor necrosis factor alpha (TNF-a) and IL-10 responses in CD81 T cells. Mechanistically, induction of b-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 b-(1, 3)-glucan and a-(1, 3)-glucan, but not chitin, possess the capacity to activate the b-catenin pathway. Our data suggest that the Wnt/b-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.

Original languageEnglish (US)
Article numbere02824-21
JournalmBio
Volume12
Issue number6
DOIs
StatePublished - Dec 1 2021
Externally publishedYes

Keywords

  • Aspergillus fumigatus
  • DC-SIGN
  • Dectin-1
  • Dectin-2
  • Dendritic cells
  • PD-L1
  • Regulatory T cells
  • Wnt signaling
  • Wnt-b-catenin
  • human

ASJC Scopus subject areas

  • Microbiology
  • Virology

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