Toll-like receptor expression reveals CpG DNA as a unique microbial stimulus for plasmacytoid dendritic cells which synergizes with CD40 ligand to induce high amounts of IL-12.
Human plasmacytoid dendritic cells (DC) (PDC, CD123+) and myeloid DC (MDC, CD11c+) may be able to discriminate between distinct classes of microbial molecules based on a different pattern of Toll-like receptor (TLR) expression. TLR1-TLR9 were examined in purified PDC and MDC. TLR9, which is critically involved in the recognition of CpG motifs in mice, was present in PDC but not in MDC. TLR4, which is required for the response to LPS, was selectively expressed on MDC. Consistent with TLR expression, PDC were susceptible to stimulation by CpG oligodeoxynucleotide (ODN) but not by LPS, while MDC responded to LPS but not to CpG ODN. In PDC, CpG ODN supported survival, activation (CD80, CD86, CD40, MHC class II), chemokine production (IL-8, IP-10) and maturation (CD83). CD40 ligand (CD40L) and CpG ODN synergized to activate PDC and to stimulate the production of IFN-alpha and IL-12 including bioactive IL-12 p70. Previous incubation of PDC with IL-3 decreased the amount of CpG-induced IFN-alpha and shifted the cytokine response in favor of IL-12. CpG ODN-activated PDC showed an increased ability to stimulate proliferation of naive allogeneic CD4 T cells, butTh1 polarization of developing T cells required simultaneous activation of PDC by CD40 ligation and CpG ODN. CpG ODN-stimulated PDC expressed CCR7, which mediates homing to lymph nodes. In conclusion, our studies reveal that IL-12 p70 production by PDC is under strict control of two signals, an adequate exogenous microbial stimulus such as CpG ODN, and CD40L provided endogenously by activated T cells. Thus, CpG ODN acts as an enhancer of T cell help, while T cell-controlled restriction to foreign antigens is maintained.
Krug
A
A
Department of Internal Medicine and Division of Clinical Pharmacology, University of Munich, Munich, Germany.
Towarowski
A
A
Britsch
S
S
Rothenfusser
S
S
Hornung
V
V
Bals
R
R
Giese
T
T
Engelmann
H
H
Endres
S
S
Krieg
A M
AM
Hartmann
G
G
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D023201:CD40 Ligand / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000502:physiology*; D015226:Dinucleoside Phosphates; D029721:Drosophila Proteins; D004357:Drug Synergism; D006801:Humans; D018664:Interleukin-12 / Q000096:biosynthesis*; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D054400:Receptors, CCR7; D011956:Receptors, Cell Surface / Q000096:biosynthesis*; D019707:Receptors, Chemokine / Q000096:biosynthesis; D018417:Th1 Cells / Q000276:immunology; D051194:Toll-Like Receptor 1; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors
D000276:Adjuvants, Immunologic; D023201:CD40 Ligand; D015226:Dinucleoside Phosphates; D029721:Drosophila Proteins; D018664:Interleukin-12; D008562:Membrane Glycoproteins; D009838:Oligodeoxyribonucleotides; D054400:Receptors, CCR7; D011956:Receptors, Cell Surface; D019707:Receptors, Chemokine; D051194:Toll-Like Receptor 1; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; C515370:CCR7 protein, human; C495345:TLR4 protein, human; C495371:TLR9 protein, human; C015772:CpG dinucleotide