Selective c-Rel activation via Malt1 controls anti-fungal T_H-17 immunity by dectin-1 and dectin-2

C-type lectins dectin-1 and dectin-2 on dendritic cells elicit protective immunity against fungal infections through induction of T_H1 and T_H-17 cellular responses. Fungal recognition by dectin-1 on human dendritic cells engages the CARD9-Bcl10-Malt1 module to activate NF-κB. Here we demonstrate that Malt1 recruitment is pivotal to T_H-17 immunity by selective activation of NF-κB subunit c-Rel, which induces expression of T_H-17-polarizing cytokines IL-1β and IL-23p19. Malt1 inhibition abrogates c-Rel activation and T_H-17 immunity to Candida species. We found that Malt1-mediated activation of c-Rel is similarly essential to induction of T_H-17-polarizing cytokines by dectin-2. Whereas dectin-1 activates all NF-κB subunits, dectin-2 selectively activates c-Rel, signifying a specialized T_H-17-enhancing function for dectin-2 in anti-fungal immunity by human dendritic cells. Thus, dectin-1 and dectin-2 control adaptive T_H-17 immunity to fungi via Malt1-dependent activation of c-Rel.