TLR2 and TLR4 signaling shapes specific antibody responses to Salmonella typhi antigens

Abstract

TLR directly induce innate immune responses by sensing a variety of microbial components and are critical for the fine-tuning of subsequent adaptive immune responses. However, their impact and mechanism of action on antibody responses against bacterial antigens are not yet fully understood. Salmonella enterica serovar Typhi (S. typhi) porins have been characterized as inducers of long-lasting specific antibody responses in mice. In this report, we show that immunization of TLR4-deficient (TLR4(-/-)), myeloid differentiating gene 88-deficient and Toll/IL-R domain-containing adaptor-inducing IFN-beta-deficient mice with S. typhi porins led to significantly reduced B-cell responses. TLR2(-/-) mice, as well, showed reduced IgG titers with a more pronounced impairment in the production of IgG3 anti-porins antibodies. Adoptive transfer of TLR2(-/-)- or TLR4(-/-)-B cells into B-cell-deficient mice revealed a direct effect of TLR4 on B cells for the primary IgM response, whereas stimulation of B cells via TLR2 was important for IgG production. Furthermore, S. typhi porins were found to efficiently elicit maturation of CD11c(+) conventional DC. Taken together, S. typhi porins represent not only a suitable B-cell antigen for vaccination, but exhibit potent TLR-dependent stimulatory functions on B cells and DC, which help to further enhance and shape the antibody response.