C-type lectin receptors (CLRs) are important pattern recognition receptors involved in recognition and induction of adaptive immunity to pathogens. Certain CLRs play an important role in viral infections as they efficiently interact with viruses. However, it has become clear that deadly viruses subvert the function of CLRs to escape antiviral immunity and promote infection. In particular, viruses target CLRs to suppress or modulate type I interferons that play a central role in the innate and adaptive defense against viruses. In this review, we discuss the function of CLRs in binding to enveloped viruses like HIV-1 and Dengue virus, and how uptake and signaling cascades have decisive effects on the outcome of infection.

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. 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 (T_H-17) responses are crucial in the defence against fungal infections. Human dendritic cells (DCs) induce T_H-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 T_H-17 responses. Here we demonstrate that the signaling molecule Malt1 present in the CARD9-Bcl10-Malt1 complex is responsible for T_H-17 induction by selectively activating the NF-κB transcription factor c-Rel, which drives transcription of the T_H-17-polarizing cytokines. Inhibition of either Malt1 or c-Rel prevents T_H-17 induction in response to fungi. Furthermore, we show that the C-type lectin dectin-2 selectively activates c-Rel, signifying a specialized T_H-17-enhancing function for this C-type lectin. Thus, novel vaccination strategies that target dectin-2 or activate Malt1 can induce predominant T_H-17 responses. Since aberrant T_H-17 responses underlie the pathology of atopic dermatitis and various autoimmune diseases, Malt1 is a rational therapeutic target to attenuate anomalous adaptive immune responses.

Langerhans cells (LCs) lining the stratified epithelia and mucosal tissues are the first antigen presenting cells to encounter invading pathogens, such as viruses, bacteria and fungi. Fungal infections form a health threat especially in immuno-compromised individuals. LCs express C-type lectin Langerin that has specificity for mannose, fucose and GlcNAc structures. Little is known about the role of human Langerin in fungal infections. Our data show that Langerin interacts with both mannan and beta-glucan structures, common cell-wall carbohydrate structures of fungi. We have screened a large panel of fungi for recognition by human Langerin and, strikingly, we observed strong binding of Langerin to a variety of Candida and Saccharomyces species and Malassezia furfur, but very weak binding was observed to Cryptococcus gattii and Cryptococcus neoformans. Notably, Langerin is the primary fungal receptor on LCs, since the interaction of LCs with the different fungi was blocked by antibodies against Langerin. Langerin recognizes both mannose and beta-glucans present on fungal cell walls and our data demonstrate that Langerin is the major fungal pathogen receptor on human LCs that recognizes pathogenic and commensal fungi. Together these data may provide more insight in the role of LCs in fungal infections.

Langerhans cells (LCs) are a subset of DCs that reside in the upper respiratory tract and are ideally suited to sense respiratory virus infections. Measles virus (MV) is a highly infectious lymphotropic and myelotropic virus that enters the host via the respiratory tract. Here, we show that human primary LCs are capable of capturing MV through the C‐type lectin Langerin. Both immature and mature LCs presented MV‐derived antigens in the context of HLA class II to MV‐specific CD4⁺ T cells. Immature LCs were not susceptible to productive infection by MV and did not present endogenous viral antigens in the context of HLA class I. In contrast, mature LCs could be infected by MV and presented de novo synthesized viral antigens to MV‐specific CD8⁺ T cells. Notably, neither immature nor mature LCs were able to cross‐present exogenous UV‐inactivated MV or MV‐infected apoptotic cells. The lack of direct infection of immature LCs, and the inability of both immature and mature LCs to cross‐present MV antigens, suggest that human LCs may not be directly involved in priming MV‐specific CD8⁺ T cells. Immune activation of LCs seems a prerequisite for MV infection of LCs and subsequent CD8⁺ T‐cell priming via the endogenous antigen presentation pathway.