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Inflammatory Flt3l is essential to mobilize dendritic cells and for T cell responses during Plasmodium infection

Nature Medicine volume 19, pages 730–738 (2013)Cite this article

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Abstract

Innate sensing mechanisms trigger a variety of humoral and cellular events that are essential to adaptive immune responses. Here we describe an innate sensing pathway triggered by Plasmodium infection that regulates dendritic cell homeostasis and adaptive immunity through Flt3 ligand (Flt3l) release. Plasmodium-induced Flt3l release in mice requires Toll-like receptor (TLR) activation and type I interferon (IFN) production. We found that type I IFN supports the upregulation of xanthine dehydrogenase, which metabolizes the xanthine accumulating in infected erythrocytes to uric acid. Uric acid crystals trigger mast cells to release soluble Flt3l from a pre-synthesized membrane-associated precursor. During infection, Flt3l preferentially stimulates expansion of the CD8-α+ dendritic cell subset or its BDCA3+ human dendritic cell equivalent and has a substantial impact on the magnitude of T cell activation, mostly in the CD8+ compartment. Our findings highlight a new mechanism that regulates dendritic cell homeostasis and T cell responses to infection.

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Figure 1: Systemic increase in Flt3l amounts, Flt3-dependent bone marrow activation and dendritic cell expansion during P. chabaudi infection.
Figure 2: Role of Flt3l-responsive CD8-α+ langerin-positive dendritic cells in T cell activation during P. chabaudi infection.
Figure 3: Role of mast cells in inflammatory Flt3l release during Plasmodium infection.
Figure 4: Role of uric acid sensing by mast cells in Flt3l release, dendritic cell expansion and T cell responses during Plasmodium infection.
Figure 5: Role of TLR and type I IFN–dependent signaling in uric acid upregulation, Flt3l release, dendritic cell expansion and T cell activation during Plasmodium blood-stage infection.
Figure 6: Systemic increase in FLT3L amounts, BDCA3+ dendritic cell expansion and CD8+ T cell responses in patients infected by P. falciparum.

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References

  1. McKenna, H.J. et al. Mice lacking flt3 ligand have deficient hematopoiesis affecting hematopoietic progenitor cells, dendritic cells, and natural killer cells. Blood 95, 3489–3497 (2000).

    Article  CAS  PubMed  Google Scholar 

  2. D'Amico, A. & Wu, L. The early progenitors of mouse dendritic cells and plasmacytoid predendritic cells are within the bone marrow hemopoietic precursors expressing Flt3. J. Exp. Med. 198, 293–303 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Karsunky, H., Merad, M., Cozzio, A., Weissman, I.L. & Manz, M.G. Flt3 ligand regulates dendritic cell development from Flt3+ lymphoid and myeloid-committed progenitors to Flt3+ dendritic cells in vivo. J. Exp. Med. 198, 305–313 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Waskow, C. et al. The receptor tyrosine kinase Flt3 is required for dendritic cell development in peripheral lymphoid tissues. Nat. Immunol. 9, 676–683 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Liu, K. & Nussenzweig, M.C. Origin and development of dendritic cells. Immunol. Rev. 234, 45–54 (2010).

    Article  CAS  PubMed  Google Scholar 

  6. Geissmann, F. et al. Development of monocytes, macrophages, and dendritic cells. Science 327, 656–661 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Christensen, J.L. & Weissman, I.L. Flk-2 is a marker in hematopoietic stem cell differentiation: a simple method to isolate long-term stem cells. Proc. Natl. Acad. Sci. USA 98, 14541–14546 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Adolfsson, J. et al. Upregulation of Flt3 expression within the bone marrow Lin−Sca1+c-kit+ stem cell compartment is accompanied by loss of self-renewal capacity. Immunity 15, 659–669 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. Fogg, D.K. et al. A clonogenic bone marrow progenitor specific for macrophages and dendritic cells. Science 311, 83–87 (2006).

    Article  CAS  PubMed  Google Scholar 

  10. Onai, N. et al. Identification of clonogenic common Flt3+M-CSFR+ plasmacytoid and conventional dendritic cell progenitors in mouse bone marrow. Nat. Immunol. 8, 1207–1216 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. Liu, K. et al. In vivo analysis of dendritic cell development and homeostasis. Science 324, 392–397 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Diao, J., Winter, E., Chen, W., Cantin, C. & Cattral, M.S. Characterization of distinct conventional and plasmacytoid dendritic cell–committed precursors in murine bone marrow. J. Immunol. 173, 1826–1833 (2004).

    Article  CAS  PubMed  Google Scholar 

  13. Naik, S.H. et al. Intrasplenic steady-state dendritic cell precursors that are distinct from monocytes. Nat. Immunol. 7, 663–671 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Leisewitz, A.L. et al. Response of the splenic dendritic cell population to malaria infection. Infect. Immun. 72, 4233–4239 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sponaas, A.M. et al. Malaria infection changes the ability of splenic dendritic cell populations to stimulate antigen-specific T cells. J. Exp. Med. 203, 1427–1433 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Mackarehtschian, K. et al. Targeted disruption of the flk2/flt3 gene leads to deficiencies in primitive hematopoietic progenitors. Immunity 3, 147–161 (1995).

    Article  CAS  PubMed  Google Scholar 

  17. Belyaev, N.N. et al. Induction of an IL7-R+c-Kithi myelolymphoid progenitor critically dependent on IFN-γ signaling during acute malaria. Nat. Immunol. 11, 477–485 (2010).

    Article  CAS  PubMed  Google Scholar 

  18. Poulin, L.F. et al. Characterization of human DNGR-1+ BDCA3+ leukocytes as putative equivalents of mouse CD8α+ dendritic cells. J. Exp. Med. 207, 1261–1271 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Farrand, K.J. et al. Langerin+ CD8α+ dendritic cells are critical for cross-priming and IL-12 production in response to systemic antigens. J. Immunol. 183, 7732–7742 (2009).

    Article  CAS  PubMed  Google Scholar 

  20. Suss, G., Eichmann, K., Kury, E., Linke, A. & Langhorne, J. Roles of CD4- and CD8-bearing T lymphocytes in the immune response to the erythrocytic stages of Plasmodium chabaudi. Infect. Immun. 56, 3081–3088 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Belnoue, E. et al. On the pathogenic role of brain-sequestered αβ CD8+ T cells in experimental cerebral malaria. J. Immunol. 169, 6369–6375 (2002).

    Article  CAS  PubMed  Google Scholar 

  22. Lundie, R.J. et al. Blood-stage Plasmodium infection induces CD8+ T lymphocytes to parasite-expressed antigens, largely regulated by CD8α+ dendritic cells. Proc. Natl. Acad. Sci. USA 105, 14509–14514 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Claser, C. et al. CD8+ T cells and IFN-γ mediate the time-dependent accumulation of infected red blood cells in deep organs during experimental cerebral malaria. PLoS ONE 6, e18720 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Soule, B.P. et al. Effects of gamma radiation on FcɛRI and TLR-mediated mast cell activation. J. Immunol. 179, 3276–3286 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Berrozpe, G. et al. The W(sh), W(57), and Ph Kit expression mutations define tissue-specific control elements located between −23 and −154 kb upstream of Kit. Blood 94, 2658–2666 (1999).

    Article  CAS  PubMed  Google Scholar 

  26. Orengo, J.M. et al. Uric acid is a mediator of the Plasmodium falciparum–induced inflammatory response. PLoS ONE 4, e5194 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Orengo, J.M. et al. Plasmodium-induced inflammation by uric acid. PLoS Pathog. 4, e1000013 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Ng, G. et al. Receptor-independent, direct membrane binding leads to cell-surface lipid sorting and Syk kinase activation in dendritic cells. Immunity 29, 807–818 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kool, M. et al. An unexpected role for uric acid as an inducer of T helper 2 cell immunity to inhaled antigens and inflammatory mediator of allergic asthma. Immunity 34, 527–540 (2011).

    Article  CAS  PubMed  Google Scholar 

  30. van de Hoef, D.L. et al. Plasmodium falciparum-derived uric acid precipitates induce maturation of dendritic cells. PLoS ONE 8, e55584 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Stocker, R., Hunt, N.H. & Weidemann, M.J. Antioxidants in plasma from mice infected with Plasmodium vinckei. Biochem. Biophys. Res. Commun. 134, 152–158 (1986).

    Article  CAS  PubMed  Google Scholar 

  32. Sanni, L.A. et al. Are reactive oxygen species involved in the pathogenesis of murine cerebral malaria? J. Infect. Dis. 179, 217–222 (1999).

    Article  CAS  PubMed  Google Scholar 

  33. Das, B.S. et al. Plasma antioxidants and lipid peroxidation products in falciparum malaria. Am. J. Trop. Med. Hyg. 49, 720–725 (1993).

    Article  CAS  PubMed  Google Scholar 

  34. Lopera-Mesa, T.M. et al. Plasma uric acid levels correlate with inflammation and disease severity in Malian children with Plasmodium falciparum malaria. PLoS ONE 7, e46424 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Pichyangkul, S. et al. Malaria blood stage parasites activate human plasmacytoid dendritic cells and murine dendritic cells through a Toll-like receptor 9–dependent pathway. J. Immunol. 172, 4926–4933 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Franklin, B.S. et al. MyD88-dependent activation of dendritic cells and CD4+ T lymphocytes mediates symptoms, but is not required for the immunological control of parasites during rodent malaria. Microbes Infect. 9, 881–890 (2007).

    Article  CAS  PubMed  Google Scholar 

  37. Coban, C., Ishii, K.J., Horii, T. & Akira, S. Manipulation of host innate immune responses by the malaria parasite. Trends Microbiol. 15, 271–278 (2007).

    Article  CAS  PubMed  Google Scholar 

  38. Voisine, C., Mastelic, B., Sponaas, A.M. & Langhorne, J. Classical CD11c+ dendritic cells, not plasmacytoid dendritic cells, induce T cell responses to Plasmodium chabaudi malaria. Int. J. Parasitol. 40, 711–719 (2010).

    Article  CAS  PubMed  Google Scholar 

  39. Urban, B.C. et al. Frequencies of peripheral blood myeloid cells in healthy Kenyan children with α+ thalassemia and the sickle cell trait. Am. J. Trop. Med. Hyg. 74, 578–584 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Bachem, A. et al. Superior antigen cross-presentation and XCR1 expression define human CD11c+CD141+ cells as homologues of mouse CD8+ dendritic cells. J. Exp. Med. 207, 1273–1281 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Crozat, K. et al. The XC chemokine receptor 1 is a conserved selective marker of mammalian cells homologous to mouse CD8α+ dendritic cells. J. Exp. Med. 207, 1283–1292 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Jongbloed, S.L. et al. Human CD141+ (BDCA-3)+ dendritic cells (DCs) represent a unique myeloid DC subset that cross-presents necrotic cell antigens. J. Exp. Med. 207, 1247–1260 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ginhoux, F. et al. The origin and development of nonlymphoid tissue CD103+ DCs. J. Exp. Med. 206, 3115–3130 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Tamura, T., Kimura, K., Yuda, M. & Yui, K. Prevention of experimental cerebral malaria by Flt3 ligand during infection with Plasmodium berghei ANKA. Infect. Immun. 79, 3947–3956 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Darrasse-Jeze, G. et al. Feedback control of regulatory T cell homeostasis by dendritic cells in vivo. J. Exp. Med. 206, 1853–1862 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Eidenschenk, C. et al. Flt3 permits survival during infection by rendering dendritic cells competent to activate NK cells. Proc. Natl. Acad. Sci. USA 107, 9759–9764 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Suto, H. et al. Mast cell–associated TNF promotes dendritic cell migration. J. Immunol. 176, 4102–4112 (2006).

    Article  CAS  PubMed  Google Scholar 

  48. Shelburne, C.P. et al. Mast cells augment adaptive immunity by orchestrating dendritic cell trafficking through infected tissues. Cell Host Microbe 6, 331–342 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Dudeck, A. et al. Mast cells are key promoters of contact allergy that mediate the adjuvant effects of haptens. Immunity 34, 973–984 (2011).

    Article  CAS  PubMed  Google Scholar 

  50. de Vries, V.C. et al. Mast cell degranulation breaks peripheral tolerance. Am. J. Transplant. 9, 2270–2280 (2009).

    Article  CAS  PubMed  Google Scholar 

  51. Coban, C. et al. Pathological role of Toll-like receptor signaling in cerebral malaria. Int. Immunol. 19, 67–79 (2007).

    Article  CAS  PubMed  Google Scholar 

  52. Haque, A. et al. Type I interferons suppress CD4+ T-cell–dependent parasite control during blood-stage Plasmodium infection. Eur. J. Immunol. 41, 2688–2698 (2011).

    Article  CAS  PubMed  Google Scholar 

  53. Shi, Y., Evans, J.E. & Rock, K.L. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 425, 516–521 (2003).

    Article  CAS  PubMed  Google Scholar 

  54. Lundie, R.J. et al. Blood-stage Plasmodium berghei infection leads to short-lived parasite-associated antigen presentation by dendritic cells. Eur. J. Immunol. 40, 1674–1681 (2010).

    Article  CAS  PubMed  Google Scholar 

  55. Wykes, M.N. et al. Plasmodium strain determines dendritic cell function essential for survival from malaria. PLoS Pathog. 3, e96 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Jung, S. et al. In vivo depletion of CD11c+ dendritic cells abrogates priming of CD8+ T cells by exogenous cell-associated antigens. Immunity 17, 211–220 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. deWalick, S. et al. Cutting edge: conventional dendritic cells are the critical APC required for the induction of experimental cerebral malaria. J. Immunol. 178, 6033–6037 (2007).

    Article  CAS  PubMed  Google Scholar 

  58. GeurtsvanKessel, C.H. et al. Clearance of influenza virus from the lung depends on migratory langerin+CD11b− but not plasmacytoid dendritic cells. J. Exp. Med. 205, 1621–1634 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Hildner, K. et al. Batf3 deficiency reveals a critical role for CD8α+ dendritic cells in cytotoxic T cell immunity. Science 322, 1097–1100 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Poulin, L.F. et al. The dermis contains langerin+ dendritic cells that develop and function independently of epidermal Langerhans cells. J. Exp. Med. 204, 3119–3131 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank R. Steinman, M.P. Longhi, E. Pamer, I. Leiner and K. Marsh for helpful discussion and reagents or critical reading of the manuscript and Celldex for human recombinant FLT3L. We thank I. Lemischka (Mount Sinai School of Medicine) the for the Flt3−/− mice and B. Malissen (Centre d'Immunologie de Marseille-Luminy) for the langerin-DTR mice. We thank the children and their guardians for participation. This paper is published with the permission of the Director of the KEMRI. This work was supported in part by US National Institutes of Health grant number AI051573 and the Agency for Science, Technology and Research (Singapore). P.G. is a Centre National de la Recherche Scientifique (CNRS) investigator. B.C.U. is a Wellcome Trust Senior Research Fellow (grant 079082). M.C.N. is a Howard Hughes Medical Institute (HHMI) investigator.

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Author notes

  1. Julie Helft, Carla Claser and Stephanie Deroubaix: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Molecular Immunology, The Rockefeller University, New York, New York, USA

    Pierre Guermonprez, Stephanie Deroubaix, Anna Gazumyan, Guillaume Darasse-Jèze, Stephanie B Telerman, Gaëlle Breton, Heidi A Schreiber, Florian Klein, Alice O Kamphorst, Matthew Meredith, Rachel Niec, Constantin Takacs, David Bosque, Tom Eisenreich & Michel C Nussenzweig

  2. Department of Oncological Sciences and The Immunology Institute, Mount Sinai School of Medicine, New York, New York, USA

    Julie Helft & Miriam Merad

  3. Singapore Immunology Network, Agency for Science, Technology and Research, Biopolis, Singapore

    Carla Claser, Florent Ginhoux & Laurent Rénia

  4. Kenya Medical Research Institute (KEMRI)–Wellcome Trust Research Program, Centre for Geographical Medicine Research, Kilifi, Kenya

    Henry Karanje & Britta C Urban

  5. Center for the Study of Hepatitis C, Laboratory for Virology and Infectious Disease, The Rockefeller University, New York, New York, USA

    Natalia Frias-Staheli, Eva Billerbeck, Marcus Dorner, Charles M Rice & Alexander Ploss

  6. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA

    Melissa Swiecki & Marco Colonna

  7. Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, New York, USA

    Fadi Mikhail

  8. Department of Microbiology and Infectious Disease and Immunology Research Group, University of Calgary, Calgary, Alberta, Canada

    Aswin Hari & Yan Shi

  9. Howard Hughes Medical Institute, Chevy Chase, Maryland, USA

    Tom Eisenreich & Michel C Nussenzweig

  10. Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, UK

    Britta C Urban

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  1. Pierre Guermonprez
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Contributions

M.C.N., P.G., B.C.U., M. Merad, Y.S., F.G., L.R., J.H., C.C. and S.D. participated in the experimental design. G.B., H.A.S., N.F.-S., E.B., M.D., C.M.R., A.P. and F.K. were involved in the production and analysis of NSG humanized mice. M.S. and M.C. provided BDCA2-DTR mice. P.G., J.H., C.C., S.D., H.K., A.G., G.D.-J., S.B.T., A.O.K., M. Meredith, R.N., C.T., F.M., A.H., D.B. and T.E. conducted most of the immunological experiments in mice.

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Correspondence to Pierre Guermonprez.

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Guermonprez, P., Helft, J., Claser, C. et al. Inflammatory Flt3l is essential to mobilize dendritic cells and for T cell responses during Plasmodium infection. Nat Med 19, 730–738 (2013). https://doi.org/10.1038/nm.3197

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