Mouse CD8alpha+ DCs and human BDCA3+ DCs are major producers of IFN-lambda in response to poly IC.
Polyinosinic:polycytidylic acid (poly IC), a double-stranded RNA, is an effective adjuvant in vivo. IFN-λs (also termed IL-28/29) are potent immunomodulatory and antiviral cytokines. We demonstrate that poly IC injection in vivo induces large amounts of IFN-λ, which depended on hematopoietic cells and the presence of TLR3 (Toll-like receptor 3), IRF3 (IFN regulatory factor 3), IRF7, IFN-I receptor, Fms-related tyrosine kinase 3 ligand (FL), and IRF8 but not on MyD88 (myeloid differentiation factor 88), Rig-like helicases, or lymphocytes. Upon poly IC injection in vivo, the IFN-λ production by splenocytes segregated with cells phenotypically resembling CD8α(+) conventional dendritic cells (DCs [cDCs]). In vitro experiments revealed that CD8α(+) cDCs were the major producers of IFN-λ in response to poly IC, whereas both CD8α(+) cDCs and plasmacytoid DCs produced large amounts of IFN-λ in response to HSV-1 or parapoxvirus. The nature of the stimulus and the cytokine milieu determined whether CD8α(+) cDCs produced IFN-λ or IL-12p70. Human DCs expressing BDCA3 (CD141), which is considered to be the human counterpart of murine CD8α(+) DCs, also produced large amounts of IFN-λ upon poly IC stimulation. Thus, IFN-λ production in response to poly IC is a novel function of mouse CD8α(+) cDCs and their human equivalents.
Department of Research Immunology, Bavarian Nordic GmbH, 82152 Martinsried, Germany.
Henning
H
Lauterbach
Barbara
B
Bathke
Stefanie
S
Gilles
Claudia
C
Traidl-Hoffmann
Christian A
CA
Luber
György
G
Fejer
Marina A
MA
Freudenberg
Gayle M
GM
Davey
David
D
Vremec
Axel
A
Kallies
Li
L
Wu
Ken
K
Shortman
Paul
P
Chaplin
Mark
M
Suter
Meredith
M
O'Keeffe
Hubertus
H
Hochrein
D000818:Animals; D000954:Antigens, Surface / Q000032:analysis*; D016827:CD8 Antigens / Q000032:analysis*; D016207:Cytokines / Q000096:biosynthesis*; D003713:Dendritic Cells / Q000276:immunology*; D018258:Herpesvirus 2, Human; D006801:Humans; D007369:Interferon Inducers / Q000494:pharmacology*; D050838:Interferon Regulatory Factor-3 / Q000502:physiology; D050839:Interferon Regulatory Factor-7 / Q000502:physiology; D050835:Interferon Regulatory Factors / Q000502:physiology; D007372:Interferons; D018664:Interleukin-12 / Q000096:biosynthesis; D007378:Interleukins / Q000096:biosynthesis*; D051379:Mice; D018157:Parapoxvirus / Q000276:immunology; D011070:Poly I-C / Q000494:pharmacology*; D018180:Thrombomodulin; D051196:Toll-Like Receptor 3 / Q000502:physiology; D000099185:Interferon Regulatory Factor-8; D000095022:Interferon Lambda
D000954:Antigens, Surface; D016827:CD8 Antigens; D016207:Cytokines; D007369:Interferon Inducers; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D050835:Interferon Regulatory Factors; D007372:Interferons; D018664:Interleukin-12; D007378:Interleukins; D011070:Poly I-C; D018180:Thrombomodulin; D051196:Toll-Like Receptor 3; D000099185:Interferon Regulatory Factor-8; C409469:CD8 antigen, alpha chain; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C494233:Irf3 protein, mouse; C494235:Irf7 protein, mouse; C546931:THBD protein, human; C511668:interferon-lambda protein, mouse