2.50
Hdl Handle:
http://hdl.handle.net/10033/333737
Title:
Type I IFN signaling in CD8- DCs impairs Th1-dependent malaria immunity.
Authors:
Haque, Ashraful; Best, Shannon E; 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; Varelias, Antiopi; Hertzog, Paul J; Kalinke, Ulrich ( 0000-0003-0503-9564 ) ; Gun, Sin Yee; Rénia, Laurent; Ruedl, Christiane; MacDonald, Kelli P A; Hill, Geoffrey R; Engwerda, Christian R
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.
Citation:
Type I IFN signaling in CD8- DCs impairs Th1-dependent malaria immunity. 2014, 124 (6):2483-96 J. Clin. Invest.
Journal:
The Journal of clinical investigation
Issue Date:
2-Jun-2014
URI:
http://hdl.handle.net/10033/333737
DOI:
10.1172/JCI70698
PubMed ID:
24789914
Type:
Article
Language:
en
ISSN:
1558-8238
Appears in Collections:
publications of the department of experimental infection research ([TC] EXPI)

Full metadata record

DC FieldValue Language
dc.contributor.authorHaque, Ashrafulen
dc.contributor.authorBest, Shannon Een
dc.contributor.authorMontes de Oca, Marcelaen
dc.contributor.authorJames, Kylie Ren
dc.contributor.authorAmmerdorffer, Anneen
dc.contributor.authorEdwards, Chelsea Len
dc.contributor.authorde Labastida Rivera, Fabianen
dc.contributor.authorAmante, Fiona Hen
dc.contributor.authorBunn, Patrick Ten
dc.contributor.authorSheel, Meruen
dc.contributor.authorSebina, Ismailen
dc.contributor.authorKoyama, Motokoen
dc.contributor.authorVarelias, Antiopien
dc.contributor.authorHertzog, Paul Jen
dc.contributor.authorKalinke, Ulrichen
dc.contributor.authorGun, Sin Yeeen
dc.contributor.authorRénia, Laurenten
dc.contributor.authorRuedl, Christianeen
dc.contributor.authorMacDonald, Kelli P Aen
dc.contributor.authorHill, Geoffrey Ren
dc.contributor.authorEngwerda, Christian Ren
dc.date.accessioned2014-11-05T15:47:23Zen
dc.date.available2014-11-05T15:47:23Zen
dc.date.issued2014-06-02en
dc.identifier.citationType I IFN signaling in CD8- DCs impairs Th1-dependent malaria immunity. 2014, 124 (6):2483-96 J. Clin. Invest.en
dc.identifier.issn1558-8238en
dc.identifier.pmid24789914en
dc.identifier.doi10.1172/JCI70698en
dc.identifier.urihttp://hdl.handle.net/10033/333737en
dc.description.abstractMany 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.en
dc.language.isoenen
dc.subject.meshAnimalsen
dc.subject.meshAntigens, CD8en
dc.subject.meshDendritic Cellsen
dc.subject.meshFemaleen
dc.subject.meshImmune Toleranceen
dc.subject.meshImmunity, Cellularen
dc.subject.meshInterferon Type Ien
dc.subject.meshMalariaen
dc.subject.meshMiceen
dc.subject.meshMice, Inbred C57BLen
dc.subject.meshMice, Knockouten
dc.subject.meshMonocytesen
dc.subject.meshPlasmodium bergheien
dc.subject.meshReceptor, Interferon alpha-betaen
dc.subject.meshSignal Transductionen
dc.subject.meshTh1 Cellsen
dc.titleType I IFN signaling in CD8- DCs impairs Th1-dependent malaria immunity.en
dc.typeArticleen
dc.identifier.journalThe Journal of clinical investigationen

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