As shown previously and in this study, a wide spectrum of cells including pDCs, mDCs and macrophages [10, 45, 46, 63] produce IFN-ab in response to Ad in vitro. The present finding that in vivo, in Ad-infected mice, splenic mDCs are the major source of IFN-ab is surprising, since in mice infected with different viruses (MCMV, HSV, VSV, MHV, influenza, vaccinia and Sendai viruses) [27, 57, 58, 59, 75, 76, 77, 78] pDCs activated by the TLRs constitute the major contributors to the systemic levels of type I IFNs. In the present study the expression levels of IFN-ab mRNAs in organs and cells from Ad-infected mice suggested a dominant role for splenic mDCs in the IFN-ab response. Furthermore, the IFN response to Ad was practically absent in mice depleted of CD11c high MHC II + myeloid DCs. Also, there was a striking similarity between the IFN-ab subtypes induced by Ads in the spleen of infected mice and those induced in mDC cultures in vitro. It should be emphasized that in mice infected with VSV, in which splenic pDCs are the main IFN producers, the spectrum of in vivo induced IFN-a subtypes was markedly different [76] . Finally, the finding that the response of Ad-infected mice was completely independent of TLR signaling and strongly dependent on IFN-ab feedback provide further arguments against a major role for pDCs. In a number of viral infection models, IFN-a and -b production by pDCs was mediated by TLR7/9 [13, 19, 23] and was at least partially independent of a positive IFN-ab feedback [76, 77, 79, 80] .