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 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)-alpha, 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-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-10 and TNF-alpha 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-alpha or sCD40L, but it had no effect on IL-15, IL-18, and TNF-alpha secretion. Our results show that TNF-alpha 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.
Brossart
P
P
Department of Hematology, Oncology, and Immunology, University of Tübingen, Germany. peter.brossart@med.uni-tuebingen.de
Zobywalski
A
A
Grünebach
F
F
Behnke
L
L
Stuhler
G
G
Reichardt
V L
VL
Kanz
L
L
Brugger
W
W
D015703:Antigens, CD; D023201:CD40 Ligand; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000187:drug effects / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis / Q000276:immunology; D016753:Interleukin-10 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000494:pharmacology; D018950:Lipopolysaccharide Receptors / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000276:immunology / Q000494:pharmacology*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D018123:Receptors, Interleukin / Q000096:biosynthesis; D053701:Receptors, Interleukin-10; D012995:Solubility; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D051841:Transcription Factor RelB; D014157:Transcription Factors / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects; D000097802:CD83 Antigen
D015703:Antigens, CD; D023201:CD40 Ligand; D018925:Chemokines; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D007136:Immunoglobulins; D016753:Interleukin-10; D018950:Lipopolysaccharide Receptors; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D018123:Receptors, Interleukin; D053701:Receptors, Interleukin-10; D051841:Transcription Factor RelB; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000097802:CD83 Antigen; C497593:RELB protein, human