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.
Highlights
Chromoblastomycosis is a chronic progressive fungal infection of mammalian skin and subcutaneous tissue that is caused byC 2015 The Authors
F. pedrosoi is recognized by the C-type lectin receptors (CLRs) Dectin-1 and Mincle, yet fails to induce the production of proinflammatory TNF-α by macrophages and DCs
To investigate whether CLR engagement by F. pedrosoi spores induces the production of cytokines that foster the differentiation of anti-fungal T cells, we cocultured BMDCs and spores and measured the production of IL-6, which is a critical priming cytokine for Th17 cells
Summary
Chromoblastomycosis is a chronic progressive fungal infection of mammalian skin and subcutaneous tissue that is caused byC 2015 The Authors. Innate immunity mediated by neutrophils and macrophages is thought to be principally responsible for host protection [2, 3]. The chronic nature of infection with F. pedrosoi may be due to an inappropriate innate immune response [8]. F. pedrosoi is recognized by the C-type lectin receptors (CLRs) Dectin-1 and Mincle, yet fails to induce the production of proinflammatory TNF-α by macrophages and DCs. Inflammatory responses to F. pedrosoi and clearance of infection can be reinstated by exogenous TLR costimulation [8]. Since there is some evidence that CD4+ but not CD8+ T cells can mediate protective host immunity against F. pedrosoi infection [3, 10] we were interested in understanding whether costimulation of the TLR receptors augments adaptive CD4+ T-cell responses in a similar fashion as we have reported for the innate cytokine responses [8]. In order to monitor and enumerate fungus-specific CD4+ T-cell responses we evaluated whether recently generated
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