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 TH1 and TH-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 TH-17 immunity by selective activation of NF-κB subunit c-Rel, which induces expression of TH-17-polarizing cytokines IL-1β and IL-23p19. Malt1 inhibition abrogates c-Rel activation and TH-17 immunity to Candida species. We found that Malt1-mediated activation of c-Rel is similarly essential to induction of TH-17-polarizing cytokines by dectin-2. Whereas dectin-1 activates all NF-κB subunits, dectin-2 selectively activates c-Rel, signifying a specialized TH-17-enhancing function for dectin-2 in anti-fungal immunity by human dendritic cells. Thus, dectin-1 and dectin-2 control adaptive TH-17 immunity to fungi via Malt1-dependent activation of c-Rel.
Author Summary Fungal infections are a major health threat and the incidence is growing worldwide. There is a need for efficient antifungal vaccines. Adaptive immune responses and in particular T helper cell type 17 (TH-17) responses are crucial in the defence against fungal infections. Human dendritic cells (DCs) induce TH-17 responses after interaction with fungi. DCs express C-type lectins dectin-1 and dectin-2 that interact with the carbohydrate structures present in the cell-wall of fungi. It is unclear how signaling by these C-type lectins leads to specific TH-17 responses. Here we demonstrate that the signaling molecule Malt1 present in the CARD9-Bcl10-Malt1 complex is responsible for TH-17 induction by selectively activating the NF-κB transcription factor c-Rel, which drives transcription of the TH-17-polarizing cytokines. Inhibition of either Malt1 or c-Rel prevents TH-17 induction in response to fungi. Furthermore, we show that the C-type lectin dectin-2 selectively activates c-Rel, signifying a specialized TH-17-enhancing function for this C-type lectin. Thus, novel vaccination strategies that target dectin-2 or activate Malt1 can induce predominant TH-17 responses. Since aberrant TH-17 responses underlie the pathology of atopic dermatitis and various autoimmune diseases, Malt1 is a rational therapeutic target to attenuate anomalous adaptive immune responses.