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Type I IFN signaling in CD8- DCs impairs Th1-dependent malaria immunity.
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
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
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2014-06-02
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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.
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Type I IFN signaling in CD8- DCs impairs Th1-dependent malaria immunity. 2014, 124 (6):2483-96 J. Clin. Invest.
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en
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1558-8238