Type I IFN signaling in CD8– DCs impairs Th1-dependent malaria immunity
Ashraful Haque, … , Geoffrey R. Hill, Christian R. Engwerda
Ashraful Haque, … , Geoffrey R. Hill, Christian R. Engwerda
Published May 1, 2014
Citation Information: J Clin Invest. 2014;124(6):2483-2496. https://doi.org/10.1172/JCI70698.
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Research Article Infectious disease Article has an altmetric score of 11

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

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.

Authors

Ashraful Haque, Shannon E. Best, Marcela Montes de Oca, Kylie R. James, Anne Ammerdorffer, Chelsea L. Edwards, Fabian de Labastida Rivera, Fiona H. Amante, Patrick T. Bunn, Meru Sheel, Ismail Sebina, Motoko Koyama, Antiopi Varelias, Paul J. Hertzog, Ulrich Kalinke, Sin Yee Gun, Laurent Rénia, Christiane Ruedl, Kelli P.A. MacDonald, Geoffrey R. Hill, Christian R. Engwerda

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Figure 4

Type I IFN signaling suppresses in vivo Th1 responses independently of CD8+ splenic cDCs.

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Type I IFN signaling suppresses in vivo Th1 responses independently of C...
(A) 50:50 WT (CD45.1+)/Ifnar1–/– (CD45.2+) mixed BM chimeric mice (n = 6–8), either uninfected or infected 4 days previously with PbA, were injected i.v. with FITC+ beads. 3 hours later, WT and Ifnar1–/– splenic cDC (CD11chiMHCIIhiTCRβ–B220– single cells) subsets (CD8+ and CD8–) were assessed by flow cytometry for uptake of FITC+ beads. Percentages indicate proportion of each cDC population containing at least one bead (2 independent experiments). (B) C57BL/6 langerin-DTR mice were administered DT or control saline, prior to and during PbA infection; PbA-infected, DT-treated mice were also treated with α-IFNAR1 or control IgG. (A group of mice was also left uninfected and nontreated.) 4 days p.i., flow cytometric analysis of the proportion of splenic CD11chiMHCIIhiTCRβ–B220– cDCs expressing CD8α as well as cell surface CD86 expression by CD8– cDCs and the number of CD4+ TCRβ+ cells expressing T-bet and IFN-γ (without ex vivo stimulation) were assessed (2 independent experiments). (C) The percentage of splenic CD4+ T cells making IFN-γ directly ex vivo from Clec9a-DTR (C57BL/6 × BALB/c F1 background) mice treated with DT, infected for 4 days with PbA, and treated with α-IFNAR1 or control IgG (experiment performed once). **P < 0.01; ***P < 0.001.