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

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. © 2008 Wiley-VCH Verlag GmbH & Co. KGaA.