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and CD40 Ligand Antagonize the Inhibitory Effects of Interleukin 10 on T-Cell Stimulatory Capacity of Dendritic Cells1
Department of Hematology, Oncology, and Immunology, University of Tübingen, D-72076 Tübingen, Germany
Interleukin (IL)-10 secretion by tumor cells was demonstrated to be one
of the mechanisms by which tumor cells can escape immunological
recognition and destruction. In dendritic cells (DCs), which are
currently used for vaccination therapies for malignant diseases, IL-10
inhibits IL-12 production and induces a state of antigen-specific
anergy in CD4- and CD8-positive T cells. We therefore analyzed the
effects of different activation stimuli including lipopolysaccharide
(LPS), tumor necrosis factor (TNF)-
, and CD40 ligation on IL-10
mediated inhibition of DC development and stimulatory capacity. In our
study, the addition of IL-10 to the cultures containing
granulocyte/macrophage-colony stimulating factor and IL-4 with or
without LPS completely inhibited the generation of DCs from peripheral
blood monocytes. These cells remained CD14 positive and expressed high
levels of IL-10 receptor (IL-10R), suggesting that IL-10 mediates its
effects by up-regulating the IL-10R. In contrast, the simultaneous
incubation of monocytes with IL-10 and TNF- 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-10 and TNF- or sCD40L elicited efficient
CTL responses against viral and tumor-associated peptide antigens,
which, however, were reduced as compared with DC cultures generated
without IL-10. IL-10 decreased the production of IL-6 and the
expression of IL-12 in the presence of TNF- or sCD40L, but it had no
effect on IL-15, IL-18, and TNF- secretion. Our results show that
TNF- or CD40 ligation can antagonize the IL-10-mediated inhibition
on DC function, suggesting that depending on activation stimuli, the
presence of IL-10 does not necessarily result in T-cell anergy.
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