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

• Main 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.
• Other Authors: School of Biological Sciences
• Format: Article
• Language: English
• Published: 2014
• Subjects: DRNTU::Science::Medicine
• Online Access: https://hdl.handle.net/10356/80006; http://hdl.handle.net/10220/20014
• Institution: Nanyang Technological University

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.