Abstract
The non-pathogenic TH17 subset of helper T cells clears fungal infections, whereas pathogenic TH17 cells cause inflammation and tissue damage; however, the mechanisms controlling these distinct responses remain unclear. Here we found that fungi sensing by the C-type lectin dectin-1 in human dendritic cells (DCs) directed the polarization of non-pathogenic TH17 cells. Dectin-1 signaling triggered transient and intermediate expression of interferon (IFN)-β in DCs, which was mediated by the opposed activities of transcription factors IRF1 and IRF5. IFN-β-induced signaling led to integrin αvβ8 expression directly and to the release of the active form of the cytokine transforming growth factor (TGF)-β indirectly. Uncontrolled IFN-β responses as a result of IRF1 deficiency induced high expression of the IFN-stimulated gene BST2 in DCs and restrained TGF-β activation. Active TGF-β was required for polarization of non-pathogenic TH17 cells, whereas pathogenic TH17 cells developed in the absence of active TGF-β. Thus, dectin-1-mediated modulation of type I IFN responses allowed TGF-β activation and non-pathogenic TH17 cell development during fungal infections in humans.
Original language | English |
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Pages (from-to) | 1735-1748 |
Number of pages | 14 |
Journal | Nature Immunology |
Volume | 23 |
Issue number | 12 |
DOIs | |
Publication status | Published - Dec 2022 |
Keywords
- Humans
- Cytokines/metabolism
- Dendritic Cells/metabolism
- Interferon Type I/metabolism
- Lectins, C-Type/genetics
- Th17 Cells/metabolism
- Transforming Growth Factor beta/metabolism
- Mycoses/immunology