High level IL-12 production by murine dendritic cells: upregulation via MHC class II and CD40 molecules and downregulation by IL-4 and IL-10.
We have shown previously that dendritic cells (DC) produce IL-12 upon interaction with CD4+ T cells. Here we ask how this IL-12 production is induced and regulated. Quantitative PCR and in situ hybridization for IL-12 p40 and an ELISA specific for the p70 heterodimer were used to determine IL-12 production. We demonstrate that ligation of either CD40 or MHC class II molecules independently trigger IL-12 production in DC, and that IL-12 production is downregulated by IL-4 and IL-10. The levels of bioactive IL-12 that can be released by triggering with an anti-CD40 mAb or with a T cell hybridoma are high (range 260-4700 pg/ml from 1 X 10(6) DC in 72 h). The CD40-mediated pathway indicates that IL-12 production is induced in DC upon interaction with activated, CD40 ligand-expressing helper T cells, even in the absence of cognate antigen recognition. Side-by-side comparison of IL-12 production, and blocking experiments employing an anti-CD40 ligand mAb, suggest that the CD40-mediated pathway is quantitatively more significant than induction via the MHC class II molecule. The importance of the CD40/CD40 ligand interaction for IL-12 induction in DC likely contributes to the recent finding that mice lacking the CD40 ligand are impaired in mounting Th1 type cell-mediated immune responses.
Koch
F
F
Department of Dermatology, University of Innsbruck, Austria.
Stanzl
U
U
Jennewein
P
P
Janke
K
K
Heufler
C
C
Kämpgen
E
E
Romani
N
N
Schuler
G
G
D000818:Animals; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology*; D017931:DNA Primers / Q000737:chemistry; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D007111:Immunity, Cellular; D016753:Interleukin-10 / Q000502:physiology*; D018664:Interleukin-12 / Q000096:biosynthesis*; D015847:Interleukin-4 / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D013154:Spleen / Q000166:cytology; D015854:Up-Regulation
D019013:CD40 Antigens; D017931:DNA Primers; D000949:Histocompatibility Antigens Class II; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4