Type I IFN signaling in CD8- DCs impairs Th1-dependent malaria immunity.
dc.contributor.author | Haque, Ashraful | |
dc.contributor.author | Best, Shannon E | |
dc.contributor.author | Montes de Oca, Marcela | |
dc.contributor.author | James, Kylie R | |
dc.contributor.author | Ammerdorffer, Anne | |
dc.contributor.author | Edwards, Chelsea L | |
dc.contributor.author | de Labastida Rivera, Fabian | |
dc.contributor.author | Amante, Fiona H | |
dc.contributor.author | Bunn, Patrick T | |
dc.contributor.author | Sheel, Meru | |
dc.contributor.author | Sebina, Ismail | |
dc.contributor.author | Koyama, Motoko | |
dc.contributor.author | Varelias, Antiopi | |
dc.contributor.author | Hertzog, Paul J | |
dc.contributor.author | Kalinke, Ulrich | |
dc.contributor.author | Gun, Sin Yee | |
dc.contributor.author | Rénia, Laurent | |
dc.contributor.author | Ruedl, Christiane | |
dc.contributor.author | MacDonald, Kelli P A | |
dc.contributor.author | Hill, Geoffrey R | |
dc.contributor.author | Engwerda, Christian R | |
dc.date.accessioned | 2014-11-05T15:47:23Z | en |
dc.date.available | 2014-11-05T15:47:23Z | en |
dc.date.issued | 2014-06-02 | en |
dc.identifier.citation | Type I IFN signaling in CD8- DCs impairs Th1-dependent malaria immunity. 2014, 124 (6):2483-96 J. Clin. Invest. | en |
dc.identifier.issn | 1558-8238 | en |
dc.identifier.pmid | 24789914 | en |
dc.identifier.doi | 10.1172/JCI70698 | en |
dc.identifier.uri | http://hdl.handle.net/10033/333737 | en |
dc.description.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. | |
dc.language.iso | en | en |
dc.subject.mesh | Animals | en |
dc.subject.mesh | Antigens, CD8 | en |
dc.subject.mesh | Dendritic Cells | en |
dc.subject.mesh | Female | en |
dc.subject.mesh | Immune Tolerance | en |
dc.subject.mesh | Immunity, Cellular | en |
dc.subject.mesh | Interferon Type I | en |
dc.subject.mesh | Malaria | en |
dc.subject.mesh | Mice | en |
dc.subject.mesh | Mice, Inbred C57BL | en |
dc.subject.mesh | Mice, Knockout | en |
dc.subject.mesh | Monocytes | en |
dc.subject.mesh | Plasmodium berghei | en |
dc.subject.mesh | Receptor, Interferon alpha-beta | en |
dc.subject.mesh | Signal Transduction | en |
dc.subject.mesh | Th1 Cells | en |
dc.title | Type I IFN signaling in CD8- DCs impairs Th1-dependent malaria immunity. | en |
dc.type | Article | en |
dc.identifier.journal | The Journal of clinical investigation | en |
refterms.dateFOA | 2018-06-12T22:07:14Z | |
html.description.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. |