IL-12p70-Dependent Th1 Induction by Human B Cells Requires Combined Activation with CD40 Ligand and CpG DNA

• Published in: The Journal of immunology (1950) 2004-01, Vol.172 (2), p.954-963
• Main Authors: Wagner, Moritz, Poeck, Hendrik, Jahrsdoerfer, Bernd, Rothenfusser, Simon, Prell, Domenik, Bohle, Barbara, Tuma, Evelyn, Giese, Thomas, Ellwart, Joachim W, Endres, Stefan, Hartmann, Gunther
• Format: Article
• Language: English
• Subjects: Adjuvants, Immunologic - physiology; B-Lymphocyte Subsets - immunology; B-Lymphocyte Subsets - metabolism; CD40 Ligand - physiology; CD40L protein; Cell Division - immunology; Cells, Cultured; CpG Islands - immunology; DNA-Binding Proteins - biosynthesis; Down-Regulation - immunology; Drug Synergism; Humans; Immunoglobulin M - biosynthesis; Immunologic Memory; Interleukin-10 - biosynthesis; Interleukin-12 - antagonists & inhibitors; Interleukin-12 - biosynthesis; Interleukin-12 - physiology; Interleukin-4 - pharmacology; Interleukin-6 - metabolism; Interphase - immunology; Lipopolysaccharides - pharmacology; Lymphocyte Activation - immunology; Membrane Glycoproteins - metabolism; Oligodeoxyribonucleotides - pharmacology; Protein Subunits - antagonists & inhibitors; Protein Subunits - biosynthesis; Protein Subunits - physiology; Receptors, Antigen, B-Cell - immunology; Receptors, Antigen, B-Cell - metabolism; Receptors, Antigen, B-Cell - physiology; Receptors, Cell Surface - biosynthesis; Receptors, Cell Surface - metabolism; T-Lymphocyte Subsets - cytology; T-Lymphocyte Subsets - immunology; Th1 Cells - immunology; Th1 Cells - metabolism; Toll-Like Receptor 4; Toll-Like Receptor 9; Toll-Like Receptors; Tumor Necrosis Factor-alpha - biosynthesis
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.172.2.954

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.