TY - JOUR
T1 - Cross-Regulation of Two Type I Interferon Signaling Pathways in Plasmacytoid Dendritic Cells Controls Anti-malaria Immunity and Host Mortality
AU - Yu, Xiao
AU - Cai, Baowei
AU - Wang, Mingjun
AU - Tan, Peng
AU - Ding, Xilai
AU - Wu, Jian
AU - Li, Jian
AU - Li, Qingtian
AU - Liu, Pinghua
AU - Xing, Changsheng
AU - Wang, Helen Y.
AU - Su, Xin zhuan
AU - Wang, Rong Fu
N1 - Funding Information:
We thank Marco Colonna (Washington University School of Medicine) for providing Tlr9 −/− mice, Richard A. Flavell (Yale University) for Tlr7 −/− mice, Kate Fitzgerald (University of Massachusetts Medical School) and Tadatsugo Taniguchi (The University of Tokyo) for Irf3 −/− :Irf7 −/− mice, Michael Gale (University of Washington) and Wenxin Wu (University of Oklahoma Health Science Center) for Ddx58 −/− mice, and Skip Virgin (Washington University at St. Louis) for Mb21d1 −/− mice, Bo Ning for art drawing, and Jana S. Burchfield for editing the manuscript. X.Y. and B.C. were partially supported by the China Scholar Council. This work was supported, in part, by grants (R01CA101795 and DA030338) from the NCI and NIDA, NIH to R.-F.W. and by the Division of Intramural Research at the National Institute of Allergy and Infectious Diseases (NIAID).
Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/11/15
Y1 - 2016/11/15
N2 - Type I interferon (IFN) is critical for controlling pathogen infection; however, its regulatory mechanisms in plasmacytoid cells (pDCs) still remain unclear. Here, we have shown that nucleic acid sensors cGAS-, STING-, MDA5-, MAVS-, or transcription factor IRF3-deficient mice produced high amounts of type I IFN-α and IFN-β (IFN-α/β) in the serum and were resistant to lethal plasmodium yoelii YM infection. Robust IFN-α/β production was abolished when gene encoding nucleic acid sensor TLR7, signaling adaptor MyD88, or transcription factor IRF7 was ablated or pDCs were depleted. Further, we identified SOCS1 as a key negative regulator to inhibit MyD88-dependent type I IFN signaling in pDCs. Finally, we have demonstrated that pDCs, cDCs, and macrophages were required for generating IFN-α/β-induced subsequent protective immunity. Thus, our findings have identified a critical regulatory mechanism of type I IFN signaling in pDCs and stage-specific function of immune cells in generating potent immunity against lethal YM infection.
AB - Type I interferon (IFN) is critical for controlling pathogen infection; however, its regulatory mechanisms in plasmacytoid cells (pDCs) still remain unclear. Here, we have shown that nucleic acid sensors cGAS-, STING-, MDA5-, MAVS-, or transcription factor IRF3-deficient mice produced high amounts of type I IFN-α and IFN-β (IFN-α/β) in the serum and were resistant to lethal plasmodium yoelii YM infection. Robust IFN-α/β production was abolished when gene encoding nucleic acid sensor TLR7, signaling adaptor MyD88, or transcription factor IRF7 was ablated or pDCs were depleted. Further, we identified SOCS1 as a key negative regulator to inhibit MyD88-dependent type I IFN signaling in pDCs. Finally, we have demonstrated that pDCs, cDCs, and macrophages were required for generating IFN-α/β-induced subsequent protective immunity. Thus, our findings have identified a critical regulatory mechanism of type I IFN signaling in pDCs and stage-specific function of immune cells in generating potent immunity against lethal YM infection.
KW - Innate immune response
KW - Malaria infection
KW - Plasmacytoid dendritic cells
KW - Type I IFN signaling
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U2 - 10.1016/j.immuni.2016.10.001
DO - 10.1016/j.immuni.2016.10.001
M3 - Article
C2 - 27793594
AN - SCOPUS:84999885091
SN - 1074-7613
VL - 45
SP - 1093
EP - 1107
JO - Immunity
JF - Immunity
IS - 5
ER -