Interferons (IFNs) are the most important cytokines in antiviral immune responses. "Natural IFN-producing cells" (IPCs) in human blood express CD4 and major histocompatibility complex class II proteins, but have not been isolated and further characterized because of their rarity, rapid apoptosis, and lack of lineage markers. Purified IPCs are here shown to be the CD4(+)CD11c- type 2 dendritic cell precursors (pDC2s), which produce 200 to 1000 times more IFN than other blood cells after microbial challenge. pDC2s are thus an effector cell type of the immune system, critical for antiviral and antitumor immune responses.

Type I interferons (IFN) and dendritic cells (DC) share an overlapping history, with rapidly accumulating evidence for vital roles for both production of type 1 IFN by DC and the interaction of this IFN both with DC and components of the innate and adaptive immune responses. Within the innate immune response, the plasmacytoid DC (pDC) are the "professional" IFN producing cells, expressing specialized toll-like receptors (TLR7 and -9) and high constitutive expression of IRF-7 that allow them to respond to viruses with rapid and extremely robust IFN production; following activation and production of IFN, the pDC subsequently mature into antigen presenting cells that help to shape the adaptive immune response. However, like most cells in the body, the myeloid or conventional DC (mDC or cDC) also produce type I IFNs, albeit typically at a lower level than that observed with pDC, and this IFN is also important in innate and adaptive immunity induced by these classic antigen presenting cells. These two major DC subsets and their IFN products interact both with each other as well as with NK cells, monocytes, T helper cells, T cytotoxic cells, T regulatory cells and B cells to orchestrate the early immune response. This review will discuss some of the converging history of DC and IFN as well as mechanisms for IFN induction in DC and the effects of this IFN on the developing immune response.

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Human mononuclear cells were previously shown to produce interferon-alpha (IFN) during 14 hr assays using herpes simplex virus type-1 infected fibroblasts [NK(HSV-FS)]. In this study, we have compared the effectors responsible for mediating NK(HSV-FS) cytolytic activity to those which produce IFN-alpha. Both activities were found to reside in non-adherent fractions, negative for non-specific esterase-staining cells. Like cells mediating NK cytolytic activity, IFN-alpha producing cells were found in light density Percoll gradient fractions. However, although NK(HSV-FS) and IFN production were largely overlapping, peak IFN production was consistently found in fractions slightly less dense than peak NK(HSV-FS) activity. IFN production was greatly augmented in fractions enriched for dendritic cells on hypertonic metrizamide gradients. The cells which produce IFN-alpha were phenotypically distinct from cytolytic NK effector cells: they lacked the Leu-11, Leu-7 and NKH1 cell surface markers shown to be present on both NK(HSV-FS) and NK(K562) effector cells. In addition, the IFN-alpha producing cells were found to be negative for a number of other markers characteristic of T cells, B cells or macrophages but were positive for Ia and HLA. The cells which produced IFN in response to UV-inactivated HSV antigen and to HSV-infected Raji cells were also found to be Leu-11 negative, and Ia positive. We conclude that the cells which produce IFN in response to HSV are a light density, Ia positive population which are distinct from NK cytolytic effector cells and co-purify with cells bearing a dendritic morphology. These results support our earlier findings that NK(HSV-FS) activity and IFN production are independent of one another and can segregate independently in vivo.

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