Skip to Content
Merck
  • Type I IFN signaling in CD8- DCs impairs Th1-dependent malaria immunity.

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

The Journal of clinical investigation (2014-05-03)
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
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
5-Carboxy-fluorescein diacetate N-succinimidyl ester, for fluorescence, ≥95.0% (HPLC)
Sigma-Aldrich
5(6)-Carboxyfluorescein diacetate N-succinimidyl ester, BioReagent, suitable for fluorescence, ≥90% (HPLC)
Sigma-Aldrich
Protease Inhibitor Cocktail powder, for general use, lyophilized powder
Sigma-Aldrich
Triton X-100, laboratory grade