TYPE-I IFNS ENHANCE THE TERMINAL DIFFERENTIATION OF DENDRITIC CELLS

This study identifies type I IFNs as activating cytokines in a serum-f ree system in which human dendritic cells (DC) were generated from CD3 4(+) progenitor cells, After 14 days of culture in GM-CSF, TNF-alpha, and IL-4, CD34(+) progenitors gave rise to a population of large, imma ture DC expressing CD1a and CD11b but lacking CD14, CD80, CD83, CD86, and CMRF44. During the next 2 wk, this population spontaneously mature d into nonadherent, CD1a(low/-), CD11b(low/-), CD14(-), CD80(+), CD83( +), CD86(+), CMRF44(+) DC with high allostimulatory activity in the ML R, To examine which factors influenced this maturation, 25 different c ytokines or factors were added to the immature DC culture. Only type I IFNs (alpha or beta) accelerated this maturation in a dose-dependent manner, so that after only 3 days the majority of large cells acquired the morphology, phenotype, and function characteristics of mature DC. Furthermore, supernatants from cultures containing spontaneously matu ring DC revealed low levels of endogenous IFN production. Because of t he similarity of the activation of DC in our culture system with the p henotypic and functional changes observed during Langerhans cells acti vation and migration in vivo, we investigated the effect of IFN-alpha on human Langerhans cell migration. IFN-alpha also activated the migra tion of human split skin-derived DC, demonstrating that this effect wa s not limited to DC derived in vitro from hemopoietic progenitor cells . DC activation by type I IFNs represents a novel mechanism of immunom odulation by these cytokines, which could be important during antivira l responses and autoimmune reactions.