Tumor necrosis factor alpha and CD40 ligand antagonize the inhibitory effects of interleukin 10 on T-cell stimulatory capacity of dendritic cells

Interleukin (IL)-10 secretion by tumor cells was demonstrated to be one of the mechanisms by which tumor cells can escape immunological recognition an d destruction. In dendritic cells (DCs), which are currently used for vacci nation therapies for malignant diseases, IL-10 inhibits IL-12 production an d induces a state of antigen-specific anergy in CD4- and CD8-positive T cel ls. We therefore analyzed the effects of different activation stimuli inclu ding lipopolysaccharide (LPS), tumor necrosis factor (TNF)-alpha, and CD40 ligation on IL-10 mediated inhibition of DC development and stimulatory cap acity. In our study, the addition of IL-10 to the cultures containing granu locyte/macrophage-colony stimulating factor and IL-4 with or without LPS co mpletely inhibited the generation of DCs from peripheral blood monocytes. T hese cells remained CD14 positive and expressed high levels of IL-10 recept or (IL-10R), suggesting that IL-10 mediates its effects by up-regulating th e IL-10R, In contrast, the simultaneous incubation of monocytes with IL-10 and TNF-alpha or soluble CD40 ligand (sCD40L) resulted in the generation of CD83-positive DCs, induction of nuclear localized RelB, and inhibition of IL-10R up-regulation, DCs grown in the presence of IL-IO and TNF-cu or sCD4 0L elicited efficient CTL responses against viral and tumor-associated pept ide antigens, which, however, were reduced as compared with DC cultures gen erated without IL-10, IL-10 decreased the production of IL-6 and the expres sion of IL-12 in the presence of TNF-alpha or sCD40L, but it had no effect on IL-15, IL-18, and TNF-alpha secretion. Out results show that TNF-alpha o r CD40 ligation can antagonize the IL-10-mediated inhibition on DC function , suggesting that depending on activation stimuli, the presence of IL-10 do es not necessarily result in T-cell anergy.