Dectin-1 signaling in neutrophils up-regulates PD-L1 and triggers ROS-mediated suppression of CD4+ T cells.

Dectin-1 is known to drive proinflammatory cytokine production by macrophages and dendritic cells which promotes Th17 CD4+ T cell responses in the setting of fungal infection. However, the role of Dectin-1 signaling in neutrophils and its impact on CD4+ T cells is not well understood. In this study, we found that neutrophils stimulated with a Dectin-1 agonist diminish CD4+ T cell viability in a rapid and reactive oxygen species (ROS)-dependent manner. Furthermore, Dectin-1 promoted neutrophil PD-L1 expression via Syk and Card9 signaling, along with other immune-checkpoint factors in a neutrophil-biased manner. Although neutrophil PD-L1 did not significantly impact disease severity in experimental autoimmune encephalomyelitis (EAE), we found that CNS-infiltrated neutrophils potently up-regulate PD-L1 expression. Furthermore, a subset of PD-L1+ neutrophils was also found to express MHC-II during EAE. In summary, we found that Dectin-1 elicits a biphasic neutrophil response in which (1) T-cell suppressive ROS is followed by (2) up-regulation of PD-L1 expression. This response may serve to limit excess CD4+ T cell-driven inflammation in infection or autoimmunity while preserving host-defense functions of neutrophils. Summary sentence: Mechanisms by which Dectin-1 signaling in neutrophils promotes a cellular phenotype with T cell-suppressive properties.

Dectin-1 limits autoimmune neuroinflammation and promotes myeloid cell-astrocyte crosstalk via Card9-independent expression of Oncostatin M.

Pathologic roles of innate immunity in neurologic disorders are well described, but their beneficial aspects are less understood. Dectin-1, a C-type lectin receptor (CLR), is largely known to induce inflammation. Here, we report that Dectin-1 limited experimental autoimmune encephalomyelitis (EAE), while its downstream signaling molecule, Card9, promoted the disease. Myeloid cells mediated the pro-resolution function of Dectin-1 in EAE with enhanced gene expression of the neuroprotective molecule, Oncostatin M (Osm), through a Card9-independent pathway, mediated by the transcription factor NFAT. Furthermore, we find that the Osm receptor (OsmR) functioned specifically in astrocytes to reduce EAE severity. Notably, Dectin-1 did not respond to heat-killed Mycobacteria, an adjuvant to induce EAE. Instead, endogenous Dectin-1 ligands, including galectin-9, in the central nervous system (CNS) were involved to limit EAE. Our study reveals a mechanism of beneficial myeloid cell-astrocyte crosstalk regulated by a Dectin-1 pathway and identifies potential therapeutic targets for autoimmune neuroinflammation.