Mouse CD8α+ DCs and human BDCA3+ DCs are major producers of IFN-λ in response to poly IC

Polyinosinic: polycytidylic acid (poly IC), a double-stranded RNA, is an effective adjuvant in vivo. IFN-lambda s (also termed IL-28/29) are potent immunomodulatory and antiviral cytokines. We demonstrate that poly IC injection in vivo induces large amounts of IFN-lambda, 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-lambda production by splenocytes segregated with cells phenotypically resembling CD8 alpha(+) conventional dendritic cells (DCs [cDCs]). In vitro experiments revealed that CD8 alpha(+) cDCs were the major producers of IFN-lambda in response to poly IC, whereas both CD8 alpha(+) cDCs and plasmacytoid DCs produced large amounts of IFN-lambda in response to HSV-1 or parapoxvirus. The nature of the stimulus and the cytokine milieu determined whether CD8 alpha(+) cDCs produced IFN-lambda or IL-12p70. Human DCs expressing BDCA3 (CD141), which is considered to be the human counterpart of murine CD8 alpha(+) DCs, also produced large amounts of IFN-lambda upon poly IC stimulation. Thus, IFN-lambda production in response to poly IC is a novel function of mouse CD8 alpha(+) cDCs and their human equivalents.