CD40‐dependent and ‐independent activation of human tonsil B cells by CpG oligodeoxynucleotides

Immunostimulatory CpG oligodeoxynucleotide (CpG‐ODN) sequences are known to directly activate B cells. We investigated the expression of the CpG receptor, Toll‐like receptor 9 (TLR9), in humantonsil B cells, and determined functional responses following stimulation by a well‐characterized stimulatory CpG‐containing ODN sequence in the human immune system, ODN 2006. Tonsil B cells were found to express high amounts of TLR9 mRNA and protein, and exposure of B cells to CpG‐ODN but not to an inactive control ODN induced a concentration‐ and time‐dependent up‐regulation of the activation markers CD23, CD25, CD40, CD54, CD80, CD86 and HLA‐DR. However, significant induction of proliferation and the release of IL‐6, IL‐10, IgG and IgM were only noted when B cells were co‐incubated with irradiated CD40L‐expressing CHO cells. Endogenous IL‐10 was identified as a critical mediator of Ig production, whereas all activating effects were independent of IL‐6. Further, CpG‐ODN counteracted IgE production induced by IL‐4. Collectively, these findings suggest a synergistic role of the TLR9/CD40 system and a critical role for the immunomodulatory cytokine IL‐10 in the orchestration of CpG‐ODN‐induced responses in B lymphocytes.