Early adenoviral gene expression mediates immunosuppression by transduced dendritic cell (DC): implications for immunotherapy using genetically modified DC.
Long-lasting, high-level gene expression in the absence of a toxic or inflammatory response to viral Ags is necessary for the successful application of genetically modified dendritic cell (DC). We previously demonstrated that efficient transduction of mature DC using DeltaE1DeltaE3 adenoviruses suppressed their stimulatory capacity for T cells. The current study was designed to investigate in more detail the suppressive effect of Ad-DC. We demonstrate that immunosuppression is not mediated by alterations in the T cell phenotype or cytokine profiles released by stimulated T cells. Also DC phenotypes are not affected. However, we demonstrate a cell cycle arrest of the T cell population stimulated by adenovirally transduced DC. Surprisingly, only freshly transduced DC are perturbed in their stimulatory capacity. Experiments using cycloheximide to block early intracellular viral gene expression showed that viral genes expressed in DC are responsible for this transient immunosuppression. In agreement with these findings, high-capacity (gutless) Ad-vectors that differ in viral gene expression from conventional DeltaE1DeltaE3 adenovirus are suitable for an efficient transduction of human DC. DC transduced with gutless Ad-vectors showed a high allostimulatory capacity for CD4(+) and CD8(+) T cells. Thus, the immunosuppressive effect of DeltaE1DeltaE3 Ad-transduced mature DC seems to be the result of early viral gene expression in DC that can be prevented using gutless Ad-vectors for transduction. These results have important implications for the use of genetically modified DC for therapeutic application.
Tuettenberg
Andrea
A
Department of Dermatology, J. Gutenberg-University, Mainz, Germany.
Jonuleit
Helmut
H
Tüting
Thomas
T
Brück
Jürgen
J
Biermann
Volker
V
Kochanek
Stefan
S
Knop
Jürgen
J
Enk
Alexander H
AH
D017498:Adenovirus E1 Proteins / Q000096:biosynthesis / Q000235:genetics; D017503:Adenovirus E3 Proteins / Q000096:biosynthesis / Q000235:genetics; D000260:Adenoviruses, Human / Q000235:genetics* / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000821:virology; D002453:Cell Cycle / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D015967:Gene Expression Regulation, Viral / Q000276:immunology*; D005822:Genetic Vectors / Q000138:chemical synthesis / Q000276:immunology*; D006131:Growth Inhibitors / Q000235:genetics / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D007165:Immunosuppression Therapy / Q000379:methods*; D007413:Intestinal Mucosa / Q000276:immunology / Q000473:pathology / Q000821:virology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D011995:Recombination, Genetic; D014161:Transduction, Genetic / Q000379:methods*
D017498:Adenovirus E1 Proteins; D017503:Adenovirus E3 Proteins; D016207:Cytokines; D006131:Growth Inhibitors