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.
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Acknowledgements
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.
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M.C.N., P.G., B.C.U., M. Merad, Y.S., F.G., L.R., J.H., C.C. and S.D. participated in the experimental design. G.B., H.A.S., N.F.-S., E.B., M.D., C.M.R., A.P. and F.K. were involved in the production and analysis of NSG humanized mice. M.S. and M.C. provided BDCA2-DTR mice. P.G., J.H., C.C., S.D., H.K., A.G., G.D.-J., S.B.T., A.O.K., M. Meredith, R.N., C.T., F.M., A.H., D.B. and T.E. conducted most of the immunological experiments in mice.
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Guermonprez, P., Helft, J., Claser, C. et al. Inflammatory Flt3l is essential to mobilize dendritic cells and for T cell responses during Plasmodium infection. Nat Med 19, 730–738 (2013). https://doi.org/10.1038/nm.3197
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DOI: https://doi.org/10.1038/nm.3197