Stimulatory and inhibitory maturation of human macrophage-derived dendritic cells.
Circulating human macrophages are often used to generate dendritic cells (DCs) by culturing them in granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin-4 (IL-4). As DCs are superb antigen-presenting cells, these types of myeloid DCs are now used in many DC-based vaccination protocols, especially in cancer, with the belief that they are essentially stimulatory or 'immunogenic'. Here we show that just as peripheral macrophage-derived myeloid DCs can be stimulatory, in vitro cultures of myeloid DCs in GM-CSF and IL-4 followed by further maturation in interferon-gamma plus bacterial superantigens (as DC maturing agents) can give rise to DCs that are functionally inhibitory. The stimulatory DCs express higher amounts of costimulatory molecules, synthesize IL-12, and efficiently stimulate naive allogeneic T cells in mixed lymphocyte reaction (MLR). The inhibitory DCs, in contrast, express lower concentrations of the critical costimulatory molecules, synthesize large amounts of IL-10, and are either marginally stimulatory or nonstimulatory in MLR. Moreover, while the stimulatory DCs further amplify proliferation of T cells in lectin-driven proliferation assays, the inhibitory DCs suppress T cell proliferation in similar assays, in vitro. Most interestingly, neutralization of the endogenously derived IL-10 with anti-IL-10 antibody with DC cultures as well as exposure of the inhibitory DCs to CpG oligonucleotides or to in vitro activated autologous CD4+ T helper cells repolarize them into stimulatory phenotype. Accordingly, these observations have important implications in translational research involving myeloid DCs.
Chakraborty
A
A
Department of Medicine, University of Connecticut School of Medicine, Farmington, Conn., USA.
Li
L
L
Chakraborty
N G
NG
Mukherji
B
B
D017951:Antigen Presentation / Q000187:drug effects; D002454:Cell Differentiation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007111:Immunity, Cellular / Q000276:immunology*; D007371:Interferon-gamma / Q000494:pharmacology; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D015847:Interleukin-4 / Q000494:pharmacology; D007959:Lymphocyte Culture Test, Mixed; D008264:Macrophages / Q000276:immunology*; D010835:Phytohemagglutinins / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000276:immunology; D018089:Superantigens / Q000494:pharmacology
D010835:Phytohemagglutinins; D018089:Superantigens; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor