IL-12-impaired and IL-12-secreting dendritic cells produce IL-23 upon CD154 restimulation.
Experimental studies in monkeys on the basis of ex vivo-generated, reinjected dendritic cells (DCs) allow investigations of primate DC biology in vivo. To study in vitro and in vivo properties of DCs with a reduced capacity to produce IL-12, we adapted findings obtained in vitro with human cells to the rhesus macaque model. Following exposure of immature monocyte-derived monkey DCs to the immunomodulating synthetic polypeptide glatiramer acetate (GA) and to dibutyryl-cAMP (d-cAMP; i.e., a cAMP enhancer that activates DCs but inhibits the induction of Th1 immune responses), the resulting DCs displayed a mature phenotype with enhanced Ag-specific T cell stimulatory function, notably also for memory Th1 cells. Phosphorylation of p38 MAPK was not induced in GA/d-cAMP-activated DCs. Accordingly, these cells secreted significantly less IL-12p40 (p < or = 0.001) than did cytokine-activated cells. However, upon restimulation with rhesus macaque CD154, GA/d-cAMP-activated DCs produced IL-12p40/IL-23. Additionally, DCs activated by proinflammatory cytokines following protocols for the generation of cells used in clinical studies secreted significantly more IL-23 upon CD154 restimulation than following prior activation. Two days after intradermal injection, GA/d-cAMP-activated fluorescence-labeled DCs were detected in the T cell areas of draining lymph nodes. When similarly injected, GA/d-cAMP as well as cytokine-activated protein-loaded DCs induced comparable Th immune responses characterized by secretion of IFN-gamma, TNF, and IL-17, and transiently expanded FOXP3(+) regulatory T cells. Reactivation of primate DCs through CD154 considerably influences their immmunostimulatory properties. This may have a substantial impact on the development of innovative vaccine approaches.
Jasny
Edith
E
Institute of Microbiology and Hygiene, Department of Infection Immunology, Charité-University Medicine Berlin, Berlin, Germany.
Eisenblätter
Martin
M
Mätz-Rensing
Kerstin
K
Tenner-Racz
Klara
K
Tenbusch
Matthias
M
Schrod
Annette
A
Stahl-Hennig
Christiane
C
Moos
Verena
V
Schneider
Thomas
T
Racz
Paul
P
Uberla
Klaus
K
Kaup
Franz-Josef
FJ
Ignatius
Ralf
R
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D003994:Bucladesine / Q000494:pharmacology; D023201:CD40 Ligand / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D000068717:Glatiramer Acetate; D006801:Humans; D007111:Immunity, Cellular; D007150:Immunohistochemistry; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism*; D053759:Interleukin-23 / Q000096:biosynthesis*; D008213:Lymphocyte Activation / Q000276:immunology; D008253:Macaca mulatta; D008856:Microscopy, Fluorescence; D010455:Peptides / Q000494:pharmacology; D010766:Phosphorylation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000276:Adjuvants, Immunologic; D016207:Cytokines; D053759:Interleukin-23; D010455:Peptides; D023201:CD40 Ligand; D018664:Interleukin-12; D000068717:Glatiramer Acetate; D003994:Bucladesine; D048051:p38 Mitogen-Activated Protein Kinases