Pathogen size alters C-type lectin receptor signaling in dendritic cells to influence CD4 Th9 cell differentiation

Dectin-1 recognizes β-glucan in fungal cell walls, and activation of Dectin-1 in dendritic cells (DCs) influences immune responses against fungi. Although many studies have shown that DCs activated via Dectin-1 induce different subsets of T helper cells according to different cytokine milieus, the mechanisms underlying such differences remain unknown. By harnessing polymorphic Candida albicans and polystyrene beads of different sizes, we find that target size influences production of cytokines that control differentiation of T helper cell subsets. Hyphal C. albicans and large beads activate DCs but cannot be phagocytosed due to their sizes, which prolongs the duration of Dectin-1 signaling. Transcriptomic analysis reveals that expression of Il33 is significantly increased by larger targets, and increased IL-33 expression promotes TH9 responses. Expression of IL-33 is regulated by the Dectin-1-SYK-PLCγ-CARD9-ERK pathway. Altogether, our study demonstrates that size of fungi can be a determining factor in how DCs induce context-appropriate adaptive immune responses. [Display omitted] •Dendritic cells exposed to C. albicans hyphae promote TH9 responses•C. albicans yeast are poor inducers of TH9 responses•Hyphal size and Dectin-1 are key factors in driving TH9 responses•Prolonged Dectin-1 signaling promotes TH9-driving IL-33 production Oh et al. show that dendritic cells exposed to C. albicans hyphae more strongly induce IL-9-producing T cells compared with cells exposed to yeast. They find that this TH9 response is driven in large part by Dectin-1 sensing microbe size, leading to elevated production of IL-33.