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 3

Type I IFN signaling in cDCs impairs Th1 priming in vivo.

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Type I IFN signaling in cDCs impairs Th1 priming in vivo. (A) FACS analy...
(A) FACS analysis of proportions, absolute numbers, and Geo Mean FL intensities for direct ex vivo IFN-γ and T-bet expression by CD4+ T cells (gated) from CD11c-Cre+ Ifnar1fl/fl mice and Ifnar1fl/fl littermate control mice (n = 7–10) infected with PbA for 4 days (2 independent experiments). (B) FACS analysis of granzyme B expression by splenic CD8+ T cells from CD11c-Cre+ Ifnar1fl/fl mice and Ifnar1fl/fl littermate control mice (n = 5) infected with PbA for 4 days. (C) WT and Ifnar1–/– mice (n = 5–8) received 1 × 105 to 2 × 105 CFSE -labeled CD4+CD45.1+ OTII cells 1 day before infection with OTII peptide–expressing PbA. 4 days p.i., splenic OTII cells were assessed for CFSE loss and, subsequently, CFSElo cells were assessed for direct ex vivo T-bet and IFN-γ expression (2 independent experiments). (D) WT mice (n = 5) were infected with PbA or left uninfected, and treated on day 2 p.i. with poly I:C or control saline. On day 3 p.i., bulk splenic cDCs were assessed by flow cytometry for cell surface CD86 expression, and on day 4 p.i., splenic CD4+TCRβ+ single cells were assessed for intracellular IFN-γ expression (without ex vivo stimulation) (performed once). (E) Number of splenic Th1 cells in CD11c-Cre+ Ifnar1fl/fl mice and Ifnar1fl/fl littermate control mice (n = 5–6) infected for 4 days with PbA and treated with poly I:C on day 2 p.i. *P < 0.05; **P < 0.01.