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

Pierre Guermonprez; Julie Helft; Carla Claser; Stephanie Deroubaix; Henry Karanje; Anna Gazumyan; Guillaume Darasse-Jèze; Stephanie B. Telerman; Gaëlle Breton; Heidi A. Schreiber; Natalia Frias-Staheli; Eva Billerbeck; Marcus Dorner; Charles M. Rice; Alexander Ploss; Florian Klein; Melissa Swiecki; Marco Colonna; Alice O. Kamphorst; Matthew Meredith; Rachel Niec; Constantin Takacs; Fadi Mikhail; Aswin Hari; David Bosque; Tom Eisenreich; Miriam Merad; Yan Shi; Florent Ginhoux; Laurent Rénia; Britta C. Urban; Michel C. Nussenzweig

doi:10.1038/nm.3197

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

Pierre Guermonprez, Julie Helft, Carla Claser, Stephanie Deroubaix, Henry Karanje, Anna Gazumyan, Guillaume Darasse-Jèze, Stephanie B. Telerman, Gaëlle Breton, Heidi A. Schreiber, Natalia Frias-Staheli, Eva Billerbeck, Marcus Dorner, Charles M. Rice, Alexander Ploss, Florian Klein, Melissa Swiecki, Marco Colonna, Alice O. Kamphorst, Matthew MeredithRachel Niec, Constantin Takacs, Fadi Mikhail, Aswin Hari, David Bosque, Tom Eisenreich, Miriam Merad, Yan Shi, Florent Ginhoux, Laurent Rénia, Britta C. Urban, Michel C. Nussenzweig

Research output: Contribution to journal › Article › peer-review

122 Scopus citations

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.

Original language	English (US)
Pages (from-to)	730-738
Number of pages	9
Journal	Nature Medicine
Volume	19
Issue number	6
DOIs	https://doi.org/10.1038/nm.3197
State	Published - Jun 2013
Externally published	Yes

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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Guermonprez, P., Helft, J., Claser, C., Deroubaix, S., Karanje, H., Gazumyan, A., Darasse-Jèze, G., Telerman, S. B., Breton, G., Schreiber, H. A., Frias-Staheli, N., Billerbeck, E., Dorner, M., Rice, C. M., Ploss, A., Klein, F., Swiecki, M., Colonna, M., Kamphorst, A. O., ... Nussenzweig, M. C. (2013). Inflammatory Flt3l is essential to mobilize dendritic cells and for T cell responses during Plasmodium infection. Nature Medicine, 19(6), 730-738. https://doi.org/10.1038/nm.3197

Guermonprez, P, Helft, J, Claser, C, Deroubaix, S, Karanje, H, Gazumyan, A, Darasse-Jèze, G, Telerman, SB, Breton, G, Schreiber, HA, Frias-Staheli, N, Billerbeck, E, Dorner, M, Rice, CM, Ploss, A, Klein, F, Swiecki, M, Colonna, M, Kamphorst, AO, Meredith, M, Niec, R, Takacs, C, Mikhail, F, Hari, A, Bosque, D, Eisenreich, T, Merad, M, Shi, Y, Ginhoux, F, Rénia, L, Urban, BC & Nussenzweig, MC 2013, 'Inflammatory Flt3l is essential to mobilize dendritic cells and for T cell responses during Plasmodium infection', Nature Medicine, vol. 19, no. 6, pp. 730-738. https://doi.org/10.1038/nm.3197

@article{610250f9ed6449e5b79251899ae44b41,

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

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.",

author = "Pierre Guermonprez and Julie Helft and Carla Claser and Stephanie Deroubaix and Henry Karanje and Anna Gazumyan and Guillaume Darasse-J{\`e}ze and Telerman, {Stephanie B.} and Ga{\"e}lle Breton and Schreiber, {Heidi A.} and Natalia Frias-Staheli and Eva Billerbeck and Marcus Dorner and Rice, {Charles M.} and Alexander Ploss and Florian Klein and Melissa Swiecki and Marco Colonna and Kamphorst, {Alice O.} and Matthew Meredith and Rachel Niec and Constantin Takacs and Fadi Mikhail and Aswin Hari and David Bosque and Tom Eisenreich and Miriam Merad and Yan Shi and Florent Ginhoux and Laurent R{\'e}nia and Urban, {Britta C.} and Nussenzweig, {Michel C.}",

note = "Funding Information: 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{\textquoteright}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.",

year = "2013",

month = jun,

doi = "10.1038/nm.3197",

language = "English (US)",

volume = "19",

pages = "730--738",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Publishing Group",

number = "6",

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T1 - Inflammatory Flt3l is essential to mobilize dendritic cells and for T cell responses during Plasmodium infection

AU - Guermonprez, Pierre

AU - Helft, Julie

AU - Claser, Carla

AU - Deroubaix, Stephanie

AU - Karanje, Henry

AU - Gazumyan, Anna

AU - Darasse-Jèze, Guillaume

AU - Telerman, Stephanie B.

AU - Breton, Gaëlle

AU - Schreiber, Heidi A.

AU - Frias-Staheli, Natalia

AU - Billerbeck, Eva

AU - Dorner, Marcus

AU - Rice, Charles M.

AU - Ploss, Alexander

AU - Klein, Florian

AU - Swiecki, Melissa

AU - Colonna, Marco

AU - Kamphorst, Alice O.

AU - Meredith, Matthew

AU - Niec, Rachel

AU - Takacs, Constantin

AU - Mikhail, Fadi

AU - Hari, Aswin

AU - Bosque, David

AU - Eisenreich, Tom

AU - Merad, Miriam

AU - Shi, Yan

AU - Ginhoux, Florent

AU - Rénia, Laurent

AU - Urban, Britta C.

AU - Nussenzweig, Michel C.

N1 - Funding Information: 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.

PY - 2013/6

Y1 - 2013/6

N2 - 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.

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

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