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Title: Type I IFN signaling in CD8– DCs impairs Th1-dependent malaria immunity
Authors: Varelias, Antiopi
Hertzog, Paul J.
Kalinke, Ulrich
Montes de Oca, Marcela
James, Kylie R.
Ammerdorffer, Anne
Edwards, Chelsea L.
de Labastida Rivera, Fabian
Amante, Fiona H.
Bunn, Patrick T.
Sheel, Meru
Sebina, Ismail
Koyama, Motoko
Haque, Ashraful
Best, Shannon E.
Gun, Sin Yee
Rénia, Laurent
Ruedl, Christiane
MacDonald, Kelli P.A.
Hill, Geoffrey R.
Engwerda, Christian R.
Keywords: DRNTU::Science::Medicine
Issue Date: 2014
Source: Haque, A., Best, S. E., Montes de Oca, M., James, K. R., Ammerdorffer, A., Edwards, C. L., et al. (2014). Type I IFN signaling in CD8– DCs impairs Th1-dependent malaria immunity. Journal of Clinical Investigation, 124(6), 2483-2496.
Series/Report no.: Journal of clinical investigation
Abstract: Many pathogens, including viruses, bacteria, and protozoan parasites, suppress cellular immune responses through activation of type I IFN signaling. Recent evidence suggests that immune suppression and susceptibility to the malaria parasite, Plasmodium, is mediated by type I IFN; however, it is unclear how type I IFN suppresses immunity to blood-stage Plasmodium parasites. During experimental severe malaria, CD4+ Th cell responses are suppressed, and conventional DC (cDC) function is curtailed through unknown mechanisms. Here, we tested the hypothesis that type I IFN signaling directly impairs cDC function during Plasmodium infection in mice. Using cDC-specific IFNAR1-deficient mice, and mixed BM chimeras, we found that type I IFN signaling directly affects cDC function, limiting the ability of cDCs to prime IFN-γ–producing Th1 cells. Although type I IFN signaling modulated all subsets of splenic cDCs, CD8– cDCs were especially susceptible, exhibiting reduced phagocytic and Th1-promoting properties in response to type I IFNs. Additionally, rapid and systemic IFN-α production in response to Plasmodium infection required type I IFN signaling in cDCs themselves, revealing their contribution to a feed-forward cytokine-signaling loop. Together, these data suggest abrogation of type I IFN signaling in CD8– splenic cDCs as an approach for enhancing Th1 responses against Plasmodium and other type I IFN–inducing pathogens.
ISSN: 0021-9738
DOI: 10.1172/JCI70698
Schools: School of Biological Sciences 
Rights: © 2014 American Society for Clinical Investigation. This paper was published in Journal of Clinical Investigation and is made available as an electronic reprint (preprint) with permission of American Society for Clinical Investigation. The paper can be found at the following official DOI:  One print or electronic copy may be made for personal use only. Systematic or multiple reproduction, distribution to multiple locations via electronic or other means, duplication of any material in this paper for a fee or for commercial purposes, or modification of the content of the paper is prohibited and is subject to penalties under law.
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:SBS Journal Articles

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