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 June 2, 2014; First published May 1, 2014
Citation Information: J Clin Invest. 2014;124(6):2483-2496. https://doi.org/10.1172/JCI70698.
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Categories: 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 7

Splenic IFN-α production depends on feed-forward, type I IFN signaling in cDCs.

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Splenic IFN-α production depends on feed-forward, type I IFN signaling i...
Assessment of serum IFN-α levels on day 4 p.i. in PbA-infected (A) WT and Ifnar1–/– mice (pooled from 2 independent experiments), (B) mice treated 1 day prior to infection with clodronate liposomes or control PBS liposomes (pooled from 2 independent experiments), and (C) CD11c-Cre+ Ifnar1fl/fl mice and Ifnar1fl/fl littermate control mice (pooled from 2 independent experiments). (D) IFN-α/β gene expression by qPCR in sorted splenic CD8– cDCs from pooled WT mice (n = 5) 3 days p.i. with PbA or naive controls. Results indicate expression relative to sorted splenic pDCs from WT infected mice on day 3 p.i. ND, not detected. **P < 0.01; ***P < 0.001.