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.

Outer Membrane Protein Complex of Meningococcus Enhances the Antipolysaccharide Antibody Response to Pneumococcal Polysaccharide–CRM197Conjugate Vaccine

“…Providing increased T cell help for PS-specific B cells that also present conjugatederived peptides to T cells may explain why simultaneous administration of our TLR2 ligand was an effective way to increase anti-PS antibody levels, while being ineffective for PS alone, in which neither B cells nor other antigen-processing cells present carrier protein-derived peptides to T cells. Indeed, B and CD4 ϩ T-cell expression of TLR2 is crucial for the antibacterial antibody response to intact S. pneumoniae cells (36).…”

“…Activation of TLR2 on B cells has recently been shown to be important for the anti-PS antibody response after pneumococcal immunization and to increase secretion of IgM (33,36,39). The results of numerous investigations suggest that engaging TLR and, particularly, TLR2 is important to anti-PS antibody responses after immunization with conjugate vaccines or challenge by whole organisms.…”

Distinct Mechanisms Underlie Boosted Polysaccharide-Specific IgG Responses Following Secondary Challenge with Intact Gram-Negative versus Gram-Positive Extracellular Bacteria

“…Four separate combinations of B cells plus T cells were injected into B cell/T cell-deficient BALB/c-scid mice, as follows: 1) naive (n)B plus nT, 2) nB plus primed(p)T, 3) pB plus nT, and 4) pB plus pT, followed by corresponding immunization with MenC or GBS-III. The number of B and CD4 + T cells adoptively transferred per mouse was based on an earlier study on T cell-dependent IgG responses in reconstituted B cell/ T cell-deficient mice (29). A separate group of scid mice received neither B or T cells as a negative control.…”

Immune response to Streptococcus pneumoniae in asthma patients: comparison between stable situation and exacerbation

“…Host defence against S. pneumoniae involves mainly acute phase responses and antibodies against surface proteins, as well as against polysaccharides. This pathogen has always been considered a T cell-independent antigen, but a number of papers describe the role of T cells in the immune response to S. pneumoniae [11][12][13][14]. The immunoglobulin (Ig)Gspecific antibody response to this bacterium depends upon CD4 T cells, B7/CD28 co-stimulation and the interaction of CD40 with its ligand, while the IgM response is T-independent [4].…”

“…Snapper et al [14] have studied many aspects of the immune response to S. pneumoniae. They have demonstrated recently in a murine model that Toll-like receptor (TLR)-2 expression by B and CD4 T cells is critical for induction of the T cell-dependent humoral immune response to intact pneumococci [13]. Evidence is also accumulating that the Th1 response is important for elimination of this pathogen, as interleukin (IL)-12-deficient patients develop serious pneumococcal infections, and interferon (IFN)-g has also been involved in the defence against this pathogen [12].…”