Shaping of adaptive immune responses to soluble proteins by TLR agonists: A role for IFN‐α/β

Abstract

Summary Toll-like receptors (TLR) are believed to play a major role in the recognition of invading organisms, although their ability to shape immune responses is not completely understood. Our aim was to investigate in vivo the effect of different TLR stimuli on the generation of antibody responses and the induction of CD8 + T-cell crosspriming after immunization with soluble protein antigens. While all TLR agonists tested elicited the production of immunomodulatory cytokines, marked differences were observed in their ability to stimulate antigen-specific immune responses. Zymosan, poly(I:C) and CpG DNA, which signal through TLR2/6, 3 and 9, respectively, were found to strongly induce the production of IgG2a antibodies, whereas R-848 (TLR7) and LPS (TLR4) did so much more weakly. In contrast, LPS, poly(I:C) and CpG DNA, but not zymosan, induced functional CD8 + T-cell responses against OVA; peptidoglycan (TLR2/?) and R-848 were also ineffective in stimulating cross-priming. Experiments using IFN-α / β R-deficient mice showed that the induction of cross-priming by LPS and poly(I:C) was abrogated in the absence of IFN-α / β signalling, and induction by CpG DNA was greatly reduced. Overall, our results identify LPS as another TLR agonist that is able to generate functional cross-priming against a soluble protein antigen. In addition, our results demonstrate that the ability of TLR stimuli to initiate CD8 + T-cell responses against soluble protein antigens is largely dependent on the IFN-α / β signalling pathway.

TLR4-dependent adjuvant activity of Neisseria meningitidis lipid A

“…Durand et al (5) demonstrated that LPS adjuvant activity was largely dependent on the IFNα/β signaling pathway. The induction of functional cross-priming to soluble protein antigens by LPS in IFNα/β-deficient mice was abrogated in the absence of IFNα/β signaling [37]. The results of our study suggest that KDO 2 linked to lipid A is crucial for TNFα induction from human macrophages, but is not required for retaining adjuvant activity in mice.…”

“…TNFα induction is MyD88-dependent [44]. In support, IL-12p70 production in mice by different microbial ligands does not correlate with IgG2a induction [37]. Macrophages exposed to unglycosylated meningococcal lipid A (kdtA) do release lower quantities of nitric oxide in a dose-dependent manner (Figure 2).…”

“…Antigen-specific antibody responses are enhanced in the presence of TLR ligands such as LPS, zymosan, CpG and poly (I:C) [37]. Durand et al showed that antibody subclasses IgG1 and IgG2a induction are greatly enhanced by TLR agonists compared to that of mice immunized with protein antigen alone [37].…”

Innate signaling regulates cross‐priming at the level of DC licensing and not antigen presentation

“…Furthermore, the ability of DC to crosspresent exogenous model antigens such as OVA in the presence of TLR ligands to CD8 1 T cells has been shown to depend on IFN-a/b receptor (IFN-a/bR) signaling. Thus, both MyD88 as well as type I IFN signaling has been shown to be important for the crosspresentation of exogenous model antigens [25][26][27][28][29].VLP as non-replicating antigens need to be cross-presented in order to prime CD8 1 T cells. We have previously shown that the immuno-dominant H-2D b restricted lymphocytic choriomeningitis virus (LCMV)-glycoprotein-derived peptide p33 coupled to VLP is efficiently cross-presented by both DC and macrophages.…”

“…Furthermore, the ability of DC to crosspresent exogenous model antigens such as OVA in the presence of TLR ligands to CD8 1 T cells has been shown to depend on IFN-a/b receptor (IFN-a/bR) signaling. Thus, both MyD88 as well as type I IFN signaling has been shown to be important for the crosspresentation of exogenous model antigens [25][26][27][28][29].…”