Fungal sensing by dectin-1 directs the non-pathogenic polarization of TH17 cells through balanced type I IFN responses in human DCs

TY - JOUR

T1 - Fungal sensing by dectin-1 directs the non-pathogenic polarization of TH17 cells through balanced type I IFN responses in human DCs

AU - Gringhuis, Sonja I

AU - Kaptein, Tanja M

AU - Remmerswaal, Ester B M

AU - Drewniak, Agata

AU - Wevers, Brigitte A

AU - Theelen, Bart

AU - D'Haens, Geert R A M

AU - Boekhout, Teun

AU - Geijtenbeek, Teunis B H

N1 - © 2022. The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

KW - Humans

KW - Cytokines/metabolism

KW - Dendritic Cells/metabolism

KW - Interferon Type I/metabolism

KW - Lectins, C-Type/genetics

KW - Th17 Cells/metabolism

KW - Transforming Growth Factor beta/metabolism

KW - Mycoses/immunology

U2 - 10.1038/s41590-022-01348-2

DO - 10.1038/s41590-022-01348-2

M3 - Article

C2 - 36456734

SN - 1529-2908

VL - 23

SP - 1735

EP - 1748

JO - Nature Immunology

JF - Nature Immunology

IS - 12

ER -