Type I IFN signaling in CD8- DCs impairs Th1-dependent malaria immunity.
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.
Ashraful
A
Haque
Shannon E
SE
Best
Marcela
M
Montes de Oca
Kylie R
KR
James
Anne
A
Ammerdorffer
Chelsea L
CL
Edwards
Fabian
F
de Labastida Rivera
Fiona H
FH
Amante
Patrick T
PT
Bunn
Meru
M
Sheel
Ismail
I
Sebina
Motoko
M
Koyama
Antiopi
A
Varelias
Paul J
PJ
Hertzog
Ulrich
U
Kalinke
Sin Yee
SY
Gun
Laurent
L
Rénia
Christiane
C
Ruedl
Kelli P A
KP
MacDonald
Geoffrey R
GR
Hill
Christian R
CR
Engwerda
D000818:Animals; D016827:CD8 Antigens / Q000378:metabolism; D003713:Dendritic Cells / Q000145:classification / Q000276:immunology*; D005260:Female; D007108:Immune Tolerance; D007111:Immunity, Cellular; D007370:Interferon Type I / Q000378:metabolism*; D008288:Malaria / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology; D010962:Plasmodium berghei / Q000276:immunology; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*
D016827:CD8 Antigens; C508032:Ifnar1 protein, mouse; D007370:Interferon Type I; D053633:Receptor, Interferon alpha-beta