CD40 ligation restores type 1 polarizing capacity  in TLR4-activated dendritic cells that have ceased  interleukin-12 expression.
Inflammation triggered by microbial lipopolysaccharide (LPS) through Toll-like receptor (TLR) 4 in the presence of interferon (IFN)-gamma induces cytokine secretion in dendritic cells (DCs) tightly regulated by a defined differentiation program. This DC differentiation is characterized not only by a dynamic immune activating but also by tolerance-inducing phenotype associated with down-modulation of cytokines previously considered to be irreversible. CD40L on activated T cells further modifies DC differentiation. Using DNA micro-arrays, we showed down-regulated mRNA levels of TLR signalling molecules, whereas CD40/CD40L signalling molecules were up-regulated at a time when LPS/IFN-gamma-activated DCs had ceased cytokine expression. Accordingly, we demonstrated that CD40/CD40L but not TLR4 or TLR3 signalling mediated by LPS or poly (cytidylic-inosinic) acid (poly I:C) and dsRNA re-established the capacity for secreting interleukin (IL)-12 in primarily LPS/IFN-gamma-activated DCs, which have exhausted their potential for cytokine secretion. The resulting TH1 polarizing DC phenotype - which lacked accompanying secretion of the crucial immune suppressive factor IL-10 - maintained the potential for activation of cytotoxic T lymphocytes (CTLs). We therefore conclude that immune modulation is restricted to a secondary T-cell-mediated stimulus at an exhausted DC state, which prevents an immune tolerant DC phenotype. These findings impact on the rational design of TLR-activated DC-based cancer vaccines for the induction of anti-tumoural CTL responses.
Michael Dohnal
Alexander
A
Laboratory of Tumor Immunology, St. Anna Children's Cancer Research Institute, Vienna, Austria.|Trimed Biotech, Vienna, Austria.
Luger
Romana
R
Laboratory of Tumor Immunology, St. Anna Children's Cancer Research Institute, Vienna, Austria.
Paul
Petra
P
Laboratory of Tumor Immunology, St. Anna Children's Cancer Research Institute, Vienna, Austria.
Fuchs
Dietmar
D
Division of Biological Chemistry, Biocenter, Innsbruck Medical University, Innsbruck, Austria.
Felzmann
Thomas
T
Laboratory of Tumor Immunology, St. Anna Children's Cancer Research Institute, Vienna, Austria.|Trimed Biotech, Vienna, Austria.
D019013:CD40 Antigens / Q000276:immunology*; D016764:Cell Polarity; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D018664:Interleukin-12 / Q000378:metabolism*; D007959:Lymphocyte Culture Test, Mixed; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000276:immunology*
D019013:CD40 Antigens; D051197:Toll-Like Receptor 4; D018664:Interleukin-12