Interferon-alpha and -beta inhibit the in vitro differentiation of immunocompetent human dendritic cells from CD14(+) precursors

Dendritic cell (DC) precursors and immature DC reside in epithelium where t hey encounter pathogens and cytokines, which stimulate their differentiatio n. We hypothesized that type-I interferons (IFN-alpha and -beta), cytokines that are produced early in the innate immune response against viruses and some bacteria, may influence DC differentiation and function. To examine th is possibility, we used an in vitro model of DC differentiation in which in itial culture of human CD14(+) monocytes with granulocyte-macrophage colony -stimulating factor (GM-CSF) and interleukin (IL)-4 generates immature DC, and subsequent culture with tumor necrosis factor (TNF)-alpha drives the fi nal development into mature DC. We found in this model that IFN-alpha/beta, added from the initiation of the culture on, significantly reduced the sur vival and altered the morphology and differentiation of DC. TNF-alpha-depen dent maturation of IFN-beta-treated immature DC led to cells with reduced e xpression of CD1a, CD40, CD54, and CD80 when compared with mature DC contro ls. IFN-alpha/ beta-treated DC further had a reduced capacity to induce nai ve Th-cell proliferation through allostimulation or anti-CDS monoclonal ant ibody stimulation. In addition, IFN-alpha/beta-treated DC secreted less IL- 12 upon stimulation with Staphylococcus aureus Cowan strain or with CD4(+) T cells, and this decrease correlated directly with their inability to supp ort CD4(+) T-cell secretion of IFN-gamma, even though T-cell lymphotoxin pr oduction was unaffected. These findings indicate that type-I IFNs can influ ence the generation of acquired immune responses by modifying T-helper cell differentiation through the regulation of DC differentiation and function. (Blood. 2000;96:210-217) (C) 2000 by The American Society of Hematology.