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

Haque, Ashraful, Best, Shannon E., De Oca, Marcela Montes, James, Kylie R., Ammerdorffer, Anne, Edwards, Chelsea L., De Labastida Rivera, Fabian, Amante, Fiona H., Bunn, Patrick T., Sheel, Meru, Sebina, Ismail, Koyama, Motoko, Varelias, Antiopi, Hertzog, Paul J., Kalinke, Ulrich, Gun, Sin Yee, Renia, Laurent, Ruedl, Christiane, MacDonald, Kelli P.A., Hill, Geoffrey R. and Engwerda, Christian R. (2014) Type I IFN signaling in CD8-DCs impairs Th1-dependent malaria immunity. Journal of Clinical Investigation, 124 6: 2483-2496. doi:10.1172/JCI70698

Author Haque, Ashraful
Best, Shannon E.
De Oca, Marcela Montes
James, Kylie R.
Ammerdorffer, Anne
Edwards, Chelsea L.
De Labastida Rivera, Fabian
Amante, Fiona H.
Bunn, Patrick T.
Sheel, Meru
Sebina, Ismail
Koyama, Motoko
Varelias, Antiopi
Hertzog, Paul J.
Kalinke, Ulrich
Gun, Sin Yee
Renia, Laurent
Ruedl, Christiane
MacDonald, Kelli P.A.
Hill, Geoffrey R.
Engwerda, Christian R.
Title Type I IFN signaling in CD8-DCs impairs Th1-dependent malaria immunity
Journal name Journal of Clinical Investigation   Check publisher's open access policy
ISSN 1558-8238
Publication date 2014-06-02
Year available 2014
Sub-type Article (original research)
DOI 10.1172/JCI70698
Open Access Status DOI
Volume 124
Issue 6
Start page 2483
End page 2496
Total pages 14
Place of publication Ann Arbor, MI, United States
Publisher American Society for Clinical Investigation
Language eng
Formatted 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.
Keyword Plasmodium
Dendritic Cells
Immune tolerance
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 1028641
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Medicine Publications
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