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Development and Functional Characterization of Murine Tolerogenic Dendritic Cells
Published on: May 18, 2018
Fonsecaea pedrosoi-induced Th17-cell differentiation in mice is fostered by Dectin-2 and suppressed by Mincle
Marcel Wüthrich1, Huafeng Wang1, Mengyi Li1
1Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, WI, USA.
Abstract:
Chromoblastomycosis is a chronic skin infection caused by the pigmented saprophytic mould Fonsecaea pedrosoi. Chronicity of infection can be broken by a coordinated innate recognition of the spores by pattern recognition receptors. While Mincle signaling via the Syk/Card9 pathway is required for fungal recognition by host cells, it is not sufficient for host control. Exogenously applied TLR agonists are necessary to promote the induction of proinflammatory cytokines and clearance of infection in vivo. Here, we investigated whether costimulation by TLR agonists fosters the development of adaptive immune responses, by examining the development of fungus-specific T cells. Subcutaneous infection of mice with F. pedrosoi spores induced the activation, expansion, and differentiation of Ag-specific CD4(+) T cells but TLR costimulation did not further augment these T-cell responses. The Dectin-2/FcRγ/Card9 signaling pathway promoted the differentiation of fungus-specific CD4(+) T cells into Th17 cells, whereas Mincle inhibited the development of this T-helper subset in infected mice. These results indicate differential roles for Dectin-2 and Mincle in the generation of adaptive immune responses to F. pedrosoi infection.
Insights
This study reveals how the immune system fights Fonsecaea pedrosoi, a fungus causing chromoblastomycosis. Dectin-2 promotes protective Th17 cells, while Mincle hinders them, offering insights into adaptive immunity against fungal skin infections.
Area of Science:
- Immunology
- Mycology
- Dermatology
Background:
- Chromoblastomycosis is a chronic fungal skin infection caused by Fonsecaea pedrosoi.
- Pattern recognition receptors are crucial for innate immune recognition of fungal spores.
- While Mincle signaling is essential for fungal recognition, it's insufficient for host control, necessitating TLR agonists for cytokine induction and infection clearance.
Purpose of the Study:
- To investigate if Toll-like receptor (TLR) agonists, when used as costimulation, enhance adaptive immune responses.
- To examine the development of fungus-specific T cells in response to Fonsecaea pedrosoi infection.
- To elucidate the differential roles of Dectin-2 and Mincle in adaptive immunity against this fungal pathogen.
Main Methods:
- Mice were subcutaneously infected with Fonsecaea pedrosoi spores.
- Activation, expansion, and differentiation of antigen-specific CD4(+) T cells were analyzed.
- The impact of TLR costimulation on T-cell responses was assessed.
- The Dectin-2/FcRγ/Card9 and Mincle signaling pathways' roles in T-cell differentiation were investigated.
Main Results:
- F. pedrosoi infection induced activation, expansion, and differentiation of Ag-specific CD4(+) T cells.
- TLR costimulation did not further augment these T-cell responses.
- The Dectin-2/FcRγ/Card9 pathway promoted the differentiation of fungus-specific CD4(+) T cells into Th17 cells.
- Mincle signaling inhibited the development of Th17 cells in infected mice.
Conclusions:
- Differential roles of Dectin-2 and Mincle in adaptive immunity to F. pedrosoi infection were identified.
- Dectin-2 signaling is important for generating protective Th17 responses against chromoblastomycosis.
- Mincle signaling may impede the development of effective adaptive immunity by inhibiting Th17 differentiation.
