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.
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, New York, USA. pierre.guermonprez@kcl.ac.uk
authors.forename: Pierre
authors.initials: P
authors.lastname: Guermonprez
authors.forename: Julie
authors.initials: J
authors.lastname: Helft
authors.forename: Carla
authors.initials: C
authors.lastname: Claser
authors.forename: Stephanie
authors.initials: S
authors.lastname: Deroubaix
authors.forename: Henry
authors.initials: H
authors.lastname: Karanje
authors.forename: Anna
authors.initials: A
authors.lastname: Gazumyan
authors.forename: Guillaume
authors.initials: G
authors.lastname: Darasse-Jèze
authors.forename: Stephanie B
authors.initials: SB
authors.lastname: Telerman
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Breton
authors.forename: Heidi A
authors.initials: HA
authors.lastname: Schreiber
authors.forename: Natalia
authors.initials: N
authors.lastname: Frias-Staheli
authors.forename: Eva
authors.initials: E
authors.lastname: Billerbeck
authors.forename: Marcus
authors.initials: M
authors.lastname: Dorner
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rice
authors.forename: Alexander
authors.initials: A
authors.lastname: Ploss
authors.forename: Florian
authors.initials: F
authors.lastname: Klein
authors.forename: Melissa
authors.initials: M
authors.lastname: Swiecki
authors.forename: Marco
authors.initials: M
authors.lastname: Colonna
authors.forename: Alice O
authors.initials: AO
authors.lastname: Kamphorst
authors.forename: Matthew
authors.initials: M
authors.lastname: Meredith
authors.forename: Rachel
authors.initials: R
authors.lastname: Niec
authors.forename: Constantin
authors.initials: C
authors.lastname: Takacs
authors.forename: Fadi
authors.initials: F
authors.lastname: Mikhail
authors.forename: Aswin
authors.initials: A
authors.lastname: Hari
authors.forename: David
authors.initials: D
authors.lastname: Bosque
authors.forename: Tom
authors.initials: T
authors.lastname: Eisenreich
authors.forename: Miriam
authors.initials: M
authors.lastname: Merad
authors.forename: Yan
authors.initials: Y
authors.lastname: Shi
authors.forename: Florent
authors.initials: F
authors.lastname: Ginhoux
authors.forename: Laurent
authors.initials: L
authors.lastname: Rénia
authors.forename: Britta C
authors.initials: BC
authors.lastname: Urban
authors.forename: Michel C
authors.initials: MC
authors.lastname: Nussenzweig
mesh_terms: D000818:Animals; D016827:CD8 Antigens / Q000032:analysis; D002465:Cell Movement; D003713:Dendritic Cells / Q000502:physiology*; D005260:Female; D006801:Humans; D007370:Interferon Type I / Q000502:physiology; D008288:Malaria / Q000276:immunology*; D008297:Male; D008407:Mast Cells / Q000502:physiology; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000276:immunology*; D051193:Toll-Like Receptors / Q000502:physiology; D014527:Uric Acid / Q000378:metabolism / Q000494:pharmacology
chemical_list: D016827:CD8 Antigens; C409469:CD8 antigen, alpha chain; D007370:Interferon Type I; D008565:Membrane Proteins; D051193:Toll-Like Receptors; C084881:flt3 ligand protein; D014527:Uric Acid