B and CD4+ T-cell expression of TLR2 is critical for optimal induction of a T-cell-dependent humoral immune response to intact Streptococcus pneumoniae

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Abstract
TLR2−/− mice immunized with Streptococcus pneumoniae (Pn) elicit normal IgM, but defective CD4+ T‐cell‐dependent type 1 IgG isotype production, associated with a largely intact innate immune response. We studied the T‐cell‐dependent phosphorylcholine (PC)‐specific IgG3 versus the T‐cell‐independent IgM response to Pn to determine whether TLR2 signals directly via the adaptive immune system. Pn‐activated TLR2−/− BMDC have only a modest defect in cytokine secretion, undergo normal maturation, and when transferred into naïve WT mice elicit a normal IgM and IgG3 anti‐PC response, relative to WT BMDC. Pn synergizes with BCR and TCR signaling for DNA synthesis in purified WT B and CD4+T cells, respectively, but is defective in cells lacking TLR2. Pn primes TLR2−/− mice for a normal CD4+ T‐cell IFN‐γ recall response. Notably, TLR2−/− B cells transferred into RAG‐2−/− mice with WT CD4+T cells, or TLR2−/− CD4+T cells transferred into athymic nude mice, each elicit a defective IgG3, in contrast to normal IgM, anti‐PC response relative to WT cells. These data are the first to demonstrate a major role for B‐cell and CD4+ T‐cell expression of TLR2 for eliciting an anti‐bacterial humoral immune response.