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

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 1

Type I IFN signaling limits Th1 responses during experimental severe malaria independently of suppressive effects on monocytes.

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Type I IFN signaling limits Th1 responses during experimental severe mal...
(A) C57BL/6 WT mice (n = 6) received α-IFNAR1 or control IgG and Ifnar1–/– mice (n = 6) received control IgG on days 0, 2, and 4 p.i. with PbA. Mice were assessed for clinical symptoms from day 5 p.i. and for survival (2 independent experiments). Dotted line at clinical score 4 indicates moribund threshold. (B) WT mice (n = 5) were infected with PbA and treated with α-IFNAR1, control IgG, or left untreated. PbA-infected Ifnar1–/– mice (n = 5) and uninfected WT and Ifnar1–/– mice (n = 5) were also tested. On day 4 p.i., flow cytometric analysis of IFN-γ production (without ex vivo stimulation) by splenic CD4+ TCRβ+ cells was performed (2 independent experiments). (C) Time course analysis of parasitemia and IFN-α protein in whole spleen lysates and sera from PbA-infected WT mice (2–5 independent experiments). (D) Gating strategy for Ly6Chi monocytes and MHCII expression in blood. WT and Ifnar1–/– mice (n = 3–5) were infected with PbA and, at time points indicated, PBMCs were assessed by flow cytometry for cell surface expression of MHCII on TCRβ–/B220–/CD11b+/Ly6Chi single cells exhibiting low granularity (2 independent experiments). (E) WT and Ccr2–/– mice (n = 5–6) were treated with α-IFNAR1 or control IgG and infected with PbA. On day 4 p.i., spleens were assessed for numbers of and, cell-surface MHCII expression by, CD11b+ Ly6Chi monocytes and (F) proportion and absolute numbers of CD4+ TCRβ+ cells producing IFN-γ without ex vivo restimulation (2 independent experiments). *P < 0.05; **P < 0.01; ***P < 0.001.