Journal Article

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

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

2013

Overview

Pierre Guermonprez and colleagues have worked out how a subset of dendritic cells expands in individuals with severe malaria. Plasmodium infection causes an accumulation of xanthine in infected red blood cells. The researchers found that type I interferon triggers an increase in the enzyme that metabolizes xanthine to uric acid. Uric acid then acts on mast cells to release Flt3 ligand, an important regulator of dendritic cells, which in turn stimulate T cells to respond to the infection. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250/2152/1566/20 / 631/250/2499 / Animals / Biological response modifiers / Biomedicine / Cancer Research / CD8 Antigens - analysis / Cell Movement / Crystals / Dehydrogenase / Dendritic cells / Dendritic Cells - physiology / Development and progression / Erythrocytes / Female / Genetic aspects / Health aspects / Homeostasis / Humans / Infectious Diseases / Inflammatory diseases / Interferon / Interferon Type I - physiology / Malaria / Malaria - immunology / Male / Mast Cells - physiology / Membrane Proteins - physiology / Metabolic Diseases / Mice / Mice, Inbred C57BL / Molecular Medicine / Neurosciences / Physiological aspects / Plasmodium / T cell receptors / T cells / T-Lymphocytes - immunology / Toll-Like Receptors - physiology / Uric Acid - metabolism / Uric Acid - pharmacology