Geijtenbeek T.B.H.: C-type lectins in infection and immunity

The research program focuses on the function of pattern recognition receptors and in particular C-type lectins on different dendritic cell (DC) subsets in adaptive immunity and infection in human. We investigate the molecular mechanisms that shape adaptive immunity to different pathogens as well as those mechanisms that are used by pathogens to infect the host. An important signaling pathway is induced by DC-SIGN triggering and this Raf-1 dependent pathway modulates Toll-like receptor signaling through post-translational modification of NF-B p65 and nucleosome remodeling to induce pathogen-tailored immunity (Gringhuis et al. Immunity 2007; Hovius et al. PLoS Pathogen 2007). This Raf-1-dependent signaling pathway is activated by different pathogens such as M. tuberculosis, M. leprae, Candida albicans, Measles virus and HIV-1 indicating that it represents a general mechanism to modulate Toll-like receptor signaling, and this might have important clinical implications. Strikingly, we have recently demonstrated that DC-SIGN induces carbohydrate specific signaling to mannose- and fucose-expressing pathogens (Gringhuis et al. Nat Immunol 2009a) which is a novel mechanism to tailor
adaptive immunity. Recent data we have identified the mechanisms that is triggered by DC-SIGN binding to fucose-expressing pathogens, which induces a very strong T helper cell type 2 response (Gringhuis et al. revised). We are currently investigating how these different pathways are involved in infection by HIV-1 (Gringhuis et al. Nat Immunol 2010) and other viruses.
Furthermore, we are investigating how C-type lectin interactions are involved in antifungal defense. We have shown that dectin-1 signaling activates the non-canonical NF-kB subunit RelB which is crucial in induction of T helper type 1 and 17 by DCs to fungi such as C. albicans (Gringhuis et al. Nat Immunol 2009b). Strikingly, recent data show that another C-type lectin Mincle counteracts Th1 induction by suppressing IL-12p35 through IRF1 degradation (Wevers et al. Cell Host&Microbe, in press). These studies suggest that C-type lectin receptors are important players in tailoring adaptive immunity to pathogens and their properties might be used in vaccination studies.
Different DC subsets are important in HIV-1 transmission and our studies have identified Langerin as a HIV-1 receptor on human LCs that protects against HIV-1 infection (de Witte et al. Nat.Med. 2007). These data indicate for the first time that Langerhans cells have an essential role in the innate defense against pathogens (De Jong et al. J.Clin.Invest. 2008). We are now identifying the molecular mechanism of Langerin-mediated restriction of LC infection and HIV-1 transmission.