IL-12p70-dependent Th1 induction by human B cells requires combined activation with CD40 ligand and CpG DNA.
The detection of microbial molecules via Toll-like receptors (TLR) in B cells is not well characterized. In this study, we found that both naive and memory B cells lack TLR4 (receptor for LPS) but express TLR9 (receptor for CpG motifs) and produce IL-6, TNF-alpha, and IL-10 upon stimulation with CpG oligonucleotides (ODN), synthetic mimics of microbial DNA. Consistent with the lack of TLR4, purified B cells failed to respond to LPS. Similar to CpG ODN, CD40 ligand (CD40L) alone induced IL-6, TNF-alpha, and IL-10. Production of these cytokines as well as IgM synthesis was synergistically increased when both CpG ODN and CD40L were combined. Unlike IL-6, TNF-alpha, and IL-10, the Th1 cytokine IL-12p70 was detected only when both CpG ODN and CD40L were present, and its induction was independent of B cell receptor cross-linking. CpG ODN did not increase the capacity of CD40L-activated B cells to induce proliferation of naive T cells. However, B cells activated with CpG ODN and CD40L strongly enhanced IFN-gamma production in developing CD4 T cells via IL-12. Together, these results demonstrate that IL-12p70 production in human B cells is under the dual control of microbial stimulation and T cell help. Our findings provide a molecular basis for the potent adjuvant activity of CpG ODN to support humoral immune responses observed in vivo, and for the limited value of LPS.
Wagner
Moritz
M
Department of Internal Medicine, Division of Clinical Pharmacology, University of Munich, Ziemssenstrasse 1, 80336 Munich, Germany.
Poeck
Hendrik
H
Jahrsdoerfer
Bernd
B
Rothenfusser
Simon
S
Prell
Domenik
D
Bohle
Barbara
B
Tuma
Evelyn
E
Giese
Thomas
T
Ellwart
Joachim W
JW
Endres
Stefan
S
Hartmann
Gunther
G
D000276:Adjuvants, Immunologic / Q000502:physiology*; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D023201:CD40 Ligand / Q000502:physiology*; D002455:Cell Division / Q000276:immunology; D002478:Cells, Cultured; D018899:CpG Islands / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D015536:Down-Regulation / Q000276:immunology; D004357:Drug Synergism; D006801:Humans; D007075:Immunoglobulin M / Q000096:biosynthesis; D007156:Immunologic Memory; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D015847:Interleukin-4 / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D007399:Interphase / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D011947:Receptors, Antigen, B-Cell / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D004268:DNA-Binding Proteins; D007075:Immunoglobulin M; D015850:Interleukin-6; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D009838:Oligodeoxyribonucleotides; D021122:Protein Subunits; D011947:Receptors, Antigen, B-Cell; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; C495371:TLR9 protein, human; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D023201:CD40 Ligand; D018664:Interleukin-12; D015847:Interleukin-4