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

Guermonprez, Pierre, Helft, Julie, Claser, Carla, Deroubaix, Stephanie, Karanje, Henry, Gazumyan, Anna, Darasse-Jèze, Guillaume, Telerman, Stephanie B, Breton, Gaëlle, Schreiber, Heidi A, Frias-Staheli, Natalia, Billerbeck, Eva, Dorner, Marcus, Rice, Charles M, Ploss, Alexander, Klein, Florian, Swiecki, Melissa, Colonna, Marco, Kamphorst, Alice O, Meredith, Matthew, Niec, Rachel, Takacs, Constantin, Mikhail, Fadi, Hari, Aswin, Bosque, David, Eisenreich, Tom, Merad, Miriam, Shi, Yan, Ginhoux, Florent, Rénia, Laurent, Urban, Britta ORCID: https://orcid.org/0000-0002-4197-8393 and Nussenzweig, Michel C (2013) 'Inflammatory Flt3l is essential to mobilize dendritic cells and for T cell responses during Plasmodium infection'. Nature Medicine, Vol 19, Issue 6, pp. 730-738.

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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.

Item Type: Article
Subjects: QW Microbiology and Immunology > Immunity by Type > QW 568 Cellular immunity. Immunologic cytotoxicity. Immunocompetence. Immunologic factors (General)
QX Parasitology > Protozoa > QX 135 Plasmodia
WH Hemic and Lymphatic Systems > Hematologic Diseases. Immunologic Factors. Blood Banks > WH 200 Leukocytes. Leukocyte disorders (General)
Faculty: Department: Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI): https://doi.org/10.1038/nm.3197
Depositing User: Martin Chapman
Date Deposited: 19 Jun 2013 12:59
Last Modified: 06 Feb 2018 13:06
URI: https://archive.lstmed.ac.uk/id/eprint/3408

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