Type I IFN signaling in CD8- DCs impairs Th1-dependent malaria immunity

Ashraful K M Nazmul Haque, Shannon E Best, Marcela Montes de Oca, Kylie R James, Anne Ammerdorffer, Chelsea L Edwards, Fabian Rivera de Labastida Rivera, Fiona H Amante, Patrick T Bunn, Meru Sheel, Ismail Sebina, Motoko Koyama, Antiopi Varelias, Paul John Hertzog, Ulrich Kalinke, Sin Yee Gun, Laurent Renia, Christiane Ruedl, Kelli P A MacDonald, Geoffrey R HillChristian R Engwerda

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50 Citations (Scopus)

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-gamma-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-alpha 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.
Original languageEnglish
Pages (from-to)2483 - 2496
Number of pages14
JournalJournal of Clinical Investigation
Volume124
Issue number6
DOIs
Publication statusPublished - 2014

Cite this

Haque, A. K. M. N., Best, S. E., Montes de Oca, M., James, K. R., Ammerdorffer, A., Edwards, C. L., ... Engwerda, C. R. (2014). Type I IFN signaling in CD8- DCs impairs Th1-dependent malaria immunity. Journal of Clinical Investigation, 124(6), 2483 - 2496. https://doi.org/10.1172/JCI70698