CpG-A oligonucleotides induce a monocyte-derived dendritic cell-like phenotype that preferentially activates CD8 T cells.
Human B cells and plasmacytoid dendritic cells recognize CpG motifs within microbial DNA via Toll-like receptor 9. Two functionally distinct types of CpG motif containing oligonucleotides (CpG ODN) have been described, CpG-A and CpG-B. In contrast to CpG-B, CpG-A induces high amounts of type I IFN (IFN-alpha and IFN-beta) in plasmacytoid dendritic cells. In the present study, we examined the effects of CpG-A on human primary monocytes. In PBMC stimulated with CpG-A and GM-CSF, monocytes showed excellent survival, increased in size and granularity, and within 3 days developed a dendritic cell-like phenotype that was characterized by down-regulation of CD14, partial up-regulation of CCR7, and an increased surface expression of costimulatory and Ag-presenting molecules. This effect could be inhibited by a combination of blocking Abs to type I IFN, and no such CpG-A-induced changes were observed in purified monocytes. Although IL-12 production by this dendritic cell-like phenotype required additional stimulation with CD40 ligand, this cell type spontaneously up-regulated IL-15 expression. Consistent with the known effect of IL-15 on effector and memory CD8 T cells, the frequency of CCR7(-)/CD45RA(-) CD8 T cells was selectively increased in allogeneic T cell assays. Furthermore, this dendritic cell type was more potent to support both the generation and the IFN-gamma production of autologous influenza matrix peptide-specific memory CD8 T cells as compared with dendritic cells generated in the presence of GM-CSF and IL-4. In conclusion, monocytes exposed to the cytokine milieu provided by CpG-A rapidly develop a dendritic cell-like phenotype that is well equipped to support CD8 T cell responses.
Krug
Anne
A
Department of Internal Medicine, Division of Clinical Pharmacology, Ludwig-Maximilians-University, Munich, Germany.
Rothenfusser
Simon
S
Selinger
S
S
Bock
C
C
Kerkmann
M
M
Battiany
J
J
Sarris
A
A
Giese
Thomas
T
Speiser
D
D
Endres
Stefan
S
Hartmann
Gunther
G
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D018899:CpG Islands / Q000276:immunology*; D017077:Culture Media, Conditioned; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007156:Immunologic Memory; D016130:Immunophenotyping; D009980:Influenza A virus / Q000276:immunology; D007370:Interferon Type I / Q000502:physiology; D007371:Interferon-gamma / Q000096:biosynthesis; D019409:Interleukin-15 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000494:pharmacology; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D009000:Monocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000276:immunology / Q000494:pharmacology*; D010446:Peptide Fragments / Q000276:immunology; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000096:biosynthesis; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000821:virology; D014763:Viral Matrix Proteins / Q000276:immunology
D000276:Adjuvants, Immunologic; C515370:CCR7 protein, human; C408982:CPG-oligonucleotide; D017077:Culture Media, Conditioned; D007370:Interferon Type I; D019409:Interleukin-15; D009838:Oligodeoxyribonucleotides; D010446:Peptide Fragments; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D014763:Viral Matrix Proteins; C448634:influenza matrix peptide (58-66); D015847:Interleukin-4; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D017493:Leukocyte Common Antigens