CD40 signalling induces IL-10-producing, tolerogenic dendritic cells.
Dendritic cells (DC) are potent antigen-presenting cells capable to induce efficient antigen-specific T cell responses in vitro and in vivo. Herein, the maturation process is of great significance, as immature DC (iDC) are known to induce rather regulatory than effector T cell differentiation. This study was designed to characterize the role of the CD40-CD40L pathway for differentiation and function of human DC. Therefore, iDC were stimulated through CD40-CD40L interaction by transduction of DC with adenoviral vectors encoding for CD40L (Ad-CD40L). Resulting DC (CD40L-DC) were analysed concerning their phenotype, cytokine profile and T cell stimulatory capacity. Transduction induced a DC phenotype comparable to stimulation with proinflammatory cytokines as revealed by upregulation of CD83 and the costimulatory molecules CD80 and CD86. Additionally, Ad-CD40L-induced strong production of IL-12p70 not observed in cytokine-matured DC. Surprisingly, the T cell stimulatory capacity was markedly reduced in CD40L-DC. Furthermore, stimulation of CD8(+) T cells by peptide-loaded CD40L-DC resulted in a substantial reduction of antigen-specific IFN-gamma production. This phenomenon is due to an enhanced IL-10 production of CD40L-DC in DC-T cell coculture as well as a stabilization of the IL-10 receptor expression on activated T cells. These data demonstrate that DC stimulated through CD40-CD40L interaction differentiate into tolerogenic DC with immunomodulatory function.
Tuettenberg
Andrea
A
Department of Dermatology, Johannes-Gutenberg-University, Mainz, Germany. tuettenberg@hautklinik.klinik.uni-mainz.de
Fondel
Sabine
S
Steinbrink
Kerstin
K
Enk
Alexander H
AH
Jonuleit
Helmut
H
D000256:Adenoviridae; D019898:Autocrine Communication; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand / Q000235:genetics / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D056747:Immunomodulation; D016753:Interleukin-10 / Q000378:metabolism*; D010641:Phenotype; D053701:Receptors, Interleukin-10 / Q000378:metabolism; D015398:Signal Transduction
D019013:CD40 Antigens; D016207:Cytokines; D053701:Receptors, Interleukin-10; D016753:Interleukin-10; D023201:CD40 Ligand