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.

Authors	Haque, Ashraful; Best, Shannon E.; de Oca, Marcela Montes; James, Kylie R.; Ammerdorffer, Anne; Edwards, Chelsea L.; Rivera, Fabian de Labastida; Amante, FH; Bunn, Patrick T.; Sheel, Meru; Sebina, Ismail; Koyama, Motoko; Varelias, Antiopi; Hertzog, Paul; Kalinke, Ulrich; Gun, Sin Yee; Renia, Laurent; Ruedl, Christiane; MacDonald, Kelli P. A.; Hill, Geoffrey R.; Engwerda, CR
Journal	THE JOURNAL OF CLINICAL INVESTIGATION
Pages	2483-96
Volume	124
Date	1/06/2014
Grant ID
Funding Body	NHMRC
URL	http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1172/JCI70698
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