Stimulatory and inhibitory differentiation of human myeloid dendritic cells

Dendritic cells (DCs) play a critical obligate role in presenting antigens to T cells for activation, In the process, upon antigen capture, DCs underg o maturation and become more stimulatory. Human myeloid DCs can be generate d from various sources, including blood, bone marrow, and CD34(+) stem cell s. As such, plastic-adherent monocytes from circulation have served as a re ady source for generating myeloid DCs in culture in granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-8 (IL-4) for translation al research in active specific immunotherapy, especially in cancer, with th e belief that they are essentially stimulatory or "immunogenic." Here we sh ow that in vitro cultures of plastic-adherent circulating monocytes in GM-C SF and IL-4 followed by further maturation in interferon-gamma plus bacteri al superantigens (DC maturing agents) can give rise to two diametrically op posite types of DCs-one stimulatory and another inhibitory. The stimulatory DCs express higher amounts of costimulatory molecules, synthesize IL-12, a nd efficiently stimulate naive allogeneic T cells in mixed lymphocyte react ion (MLR). The inhibitory DCs, in contrast, express lower concentrations of the critical costimulatory molecules, synthesize large amounts of IL-10, a nd are nonstimulatory in allogeneic primary MLR. Moreover, while the stimul atory DCs further amplify proliferation of T cells in lectin-driven prolife ration assays, the inhibitory DCs totally block T cell proliferation in sim ilar assays, in vitro. Most interestingly, neutralization of the endogenous ly derived IL-10 with anti-IL-10 antibody in DC cultures repolarizes the in hibitory DCs toward stimulatory phenotype, Accordingly, these observations have important implications in translational research involving myeloid DCs . (C) Academic Press.