foto

Prof. dr. T.B.H. Geijtenbeek

Main activities
Research
Focus of research

My research focuses on the function of C-type lectins on dendritic cell subsets in adaptive immunity and infection in humans. C-type lectins interact with carbohydrate structures expressed by pathogens and it is becoming clear that C-type lectins alone or due to crosstalk with Toll-like receptors induce signaling pathways that are crucial in the induction of innate and adaptive immunity. We are studying the role of C-type lectins such as DC-SIGN, Langerin and dectin-1 in infections with viruses (HIV-1, measles virus), mycobacteria and fungi. It is becoming clear that some pathogens such as HIV-1 subvert the function and signaling of DC-SIGN for its survival and infection of the host. Furthermore, we are investigating the function of these pattern recognition receptors in the induction of aberrant adaptive immunity in diseases such as allergy and asthma.

Key publications
  • Gringhuis SI, Hertoghs N, Kaptein TM, Zijlstra-Willems EM, Sarrami-Fooroshani R, Sprokholt JK, van Teijlingen NH, Kootstra NA, Booiman T, van Dort KA, Ribeiro CMS, Drewniak A, Geijtenbeek TBH, HIV-1 blocks the signaling adaptor MAVS to evade antiviral host defense after sensing of abortive HIV-1 RNA by the host helicase DDX3. NAT IMMUNOL 2017;18 (2):225-235 [PubMed]
  • Ribeiro CMS, Sarrami-Forooshani R, Setiawan LC, Zijlstra-Willems EM, van Hamme JL, Tigchelaar W, van der Wel NN, Kootstra NA, Gringhuis SI, Geijtenbeek TBH, Receptor usage dictates HIV-1 restriction by human TRIM5α in dendritic cell subsets. NATURE 2016;540 (7633):448-452 [PubMed]
  • Geijtenbeek TBH, Gringhuis SI, C-type lectin receptors in the control of T helper cell differentiation. NAT REV IMMUNOL 2016;16 (7):433-448 [PubMed]
  • Mesman AW, Zijlstra-Willems EM, Kaptein TM, de Swart RL, Davis ME, Ludlow M, Duprex WP, Gack MU, Gringhuis SI, Geijtenbeek TBH, Measles Virus Suppresses RIG-I-like Receptor Activation in Dendritic Cells via DC-SIGN-Mediated Inhibition of PP1 Phosphatases. CELL HOST MICROBE 2014;16 (1):31-42 [PubMed]
  • Gringhuis SI, Kaptein TM, Wevers BA, Theelen B, van der Vlist M, Boekhout T, Geijtenbeek TBH, Dectin-1 is an extracellular pathogen sensor for the induction and processing of IL-1 beta via a noncanonical caspase-8 inflammasome. NAT IMMUNOL 2012;13 (3):246-U63 [PubMed]
All Publications
Research programmes

Dendritic cells 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.

Faculty
Prof. dr. T.B.H. Geijtenbeek
Dr. S.I. Gringhuis PhD
Dr. E.M.M. van Leeuwen

Postdocs
Dr. M.J. Bunders MD
Dr. C.M.S. Ribeiro PhD

PhD Students
S. Busold
A.P.M. Cloherty MSc
L.E.H. van der Donk MSc
J. Eder
T.T.H.D. Eisden
L.C. Helgers
Drs. Z. Kruize
L.M.K. Mason
N.A. Nagy
B.M. Nijmeijer MSc
Drs. M. van der Poel (NIN)
Drs. R. Sarrami
M. Stunnenberg
N.H. van Teijlingen MA

Others
Ing. J.L. van Hamme
Ing. T.M. Kaptein MSc
Ing. E.M. Zijlstra-Willems

Current research funding
  • AMC
  • AMC (Vrijgesteld)
  • Europese Unie
  • NWO
  • Stichting Aidsfonds/SOA AIDS Nederland
  • ZonMw
  • ZonMw (Vrijgesteld)