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

被引：126

作者：

Guermonprez, Pierre ^{[1
]}

Helft, Julie ^{[2
,3
]}

Claser, Carla ^{[4
]}

Deroubaix, Stephanie ^{[1
]}

Karanje, Henry ^{[5
]}

Gazumyan, Anna ^{[1
]}

Darasse-Jeze, Guillaume ^{[1
]}

Telerman, Stephanie B. ^{[1
]}

Breton, Gaelle ^{[1
]}

Schreiber, Heidi A. ^{[1
]}

Frias-Staheli, Natalia ^{[6
]}

Billerbeck, Eva ^{[6
]}

Dorner, Marcus ^{[6
]}

Rice, Charles M. ^{[6
]}

Ploss, Alexander ^{[6
]}

Klein, Florian ^{[1
]}

Swiecki, Melissa ^{[7
]}

Colonna, Marco ^{[7
]}

Kamphorst, Alice O. ^{[1
]}

Meredith, Matthew ^{[1
]}

Niec, Rachel ^{[1
]}

Takacs, Constantin ^{[1
]}

Mikhail, Fadi ^{[8
]}

Hari, Aswin ^{[9
,10
]}

Bosque, David ^{[1
]}

Eisenreich, Tom ^{[1
,11
]}

Merad, Miriam ^{[2
,3
]}

Shi, Yan ^{[9
,10
]}

Ginhoux, Florent ^{[4
]}

Renia, Laurent ^{[4
]}

Urban, Britta C. ^{[5
,12
]}

Nussenzweig, Michel C. ^{[1
,11
]}

机构：

[1] Rockefeller Univ, Lab Mol Immunol, New York, NY 10021 USA

[2] Mt Sinai Sch Med, Dept Oncol Sci, New York, NY USA

[3] Mt Sinai Sch Med, Inst Immunol, New York, NY USA

[4] Biopolis, Agcy Sci Technol & Res, Singapore Immunol Network, Singapore, Singapore

[5] Kenya Med Res Inst KEMRI, Wellcome Trust Res Program, Ctr Geog Med Res, Kilifi, Kenya

[6] Rockefeller Univ, Lab Virol & Infect Dis, Ctr Study Hepatitis C, New York, NY 10021 USA

[7] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO USA

[8] Weill Cornell Med Coll, Dept Neurol & Neurosci, New York, NY USA

[9] Univ Calgary, Dept Microbiol & Infect Dis, Calgary, AB, Canada

[10] Univ Calgary, Immunol Res Grp, Calgary, AB, Canada

[11] Howard Hughes Med Inst, Chevy Chase, MD USA

[12] Univ Liverpool, Liverpool Sch Trop Med, Liverpool L3 5QA, Merseyside, England

来源：

NATURE MEDICINE | 2013年 / 19卷 / 06期

基金：

英国惠康基金; 美国国家卫生研究院;

关键词：

MAST-CELLS; URIC-ACID; MALARIA; PROGENITORS; LYMPHOCYTES; PRECURSORS; EXPRESSION; LIGAND; LEADS; IDENTIFICATION;

D O I：

10.1038/nm.3197

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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-alpha(+) 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.

引用

页码：730 / +

页数：10

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