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 - 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 -