Langerin is a natural barrier to HIV-1 transmission by Langerhans cells (original) (raw)

Nature Medicine volume 13, pages 367–371 (2007)Cite this article

Abstract

Human immunodeficiency virus-1 (HIV-1) is primarily transmitted sexually. Dendritic cells (DCs) in the subepithelium transmit HIV-1 to T cells through the C-type lectin DC-specific intercellular adhesion molecule (ICAM)-3-grabbing nonintegrin (DC-SIGN). However, the epithelial Langerhans cells (LCs) are the first DC subset to encounter HIV-1. It has generally been assumed that LCs mediate the transmission of HIV-1 to T cells through the C-type lectin Langerin, similarly to transmission by DC-SIGN on dendritic cells (DCs). Here we show that in stark contrast to DC-SIGN, Langerin prevents HIV-1 transmission by LCs. HIV-1 captured by Langerin was internalized into Birbeck granules and degraded. Langerin inhibited LC infection and this mechanism kept LCs refractory to HIV-1 transmission; inhibition of Langerin allowed LC infection and subsequent HIV-1 transmission. Notably, LCs also inhibited T-cell infection by viral clearance through Langerin. Thus Langerin is a natural barrier to HIV-1 infection, and strategies to combat infection must enhance, preserve or, at the very least, not interfere with Langerin expression and function.

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Acknowledgements

We thank L. Colledge, R. Mebius and M. Litjens for their comments on the manuscript, S. Santegoets for helping to set up the MUTZ3 culture, P. Gallay (Scripps Research Institute) for providing us with the pseudotyped HIV-1 viruses and S. Saeland (Schering Plough) for the Langerin plasmid. We are grateful to the Boerhaave Clinic for providing us with essential materials. We thank E.-C. Park and B. Seed (US National Institutes of Health AIDS Research and Reference Reagent Program) for providing the pSyn gp120 IgG reagent. L.d.W., A.N. and M.A.W.P.d.J. were supported by grants from the Dutch Scientific Research program (VIDI NWO 917-46-367; NWO 912-04-025); A.N. was also supported by the Dutch AIDS Foundation (20005033).

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Authors and Affiliations

  1. Department of Molecular Cell Biology and Immunology, VU University Medical Center, van de Boechorstraat 7, Amsterdam, 1081BT, The Netherlands
    Lot de Witte, Alexey Nabatov, Donna Fluitsma, Marein A W P de Jong, Yvette van Kooyk & Teunis B H Geijtenbeek
  2. Department of Dermatology and Venereology, University Hospital of Geneva, 24 Rue Micheli-du-Crest, Geneva, 1211, Switzerland
    Marjorie Pion & Vincent Piguet
  3. Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, Amsterdam, 1081HV, The Netherlands
    Tanja de Gruijl

Authors

  1. Lot de Witte
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  2. Alexey Nabatov
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  3. Marjorie Pion
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  4. Donna Fluitsma
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  5. Marein A W P de Jong
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  6. Tanja de Gruijl
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  7. Vincent Piguet
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  8. Yvette van Kooyk
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  9. Teunis B H Geijtenbeek
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Contributions

L.d.W. designed, executed and interpreted most experiments and prepared the manuscript. A.N. generated viruses and helped with several experiments. M.P. generated the Langerin lentiviral construct under supervision of V.P., who also helped with the manuscript preparation. D.F. executed and interpreted the electron microscopy analysis. M.A.W.P.d.J. helped with LC isolations. T.d.G. contributed reagents and knowledge on LC isolation. Y.v.K. provided supervision and helped with the manuscript preparation. T.B.H.G. supervised all aspects of this study including study design, execution and interpretation, and manuscript preparation.

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Correspondence toTeunis B H Geijtenbeek.

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The authors declare no competing financial interests.

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de Witte, L., Nabatov, A., Pion, M. et al. Langerin is a natural barrier to HIV-1 transmission by Langerhans cells.Nat Med 13, 367–371 (2007). https://doi.org/10.1038/nm1541

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