Synchronization of Dendritic Cell Activation and Antigen Exposure Is Required for the Induction of Th1/Th17 Responses

Abstract

The dendritic cell (DC) targeting/activation patterns required to elicit Th1/Th17 responses remain undefined. One postulated requirement was that of a physical linkage between Ags and immunomodulators. Accordingly, the separate same-site administration of Ag85B–ESAT-6 (hybrid-1 protein; H1), a mycobacterial fusion Ag, and the CAF01 liposome-based adjuvant induced similar Ab and weak Th2 responses as those of coformulated H1/CAF01 but failed to elicit Th1/Th17 responses. Yet, this separate same-site injection generated the same type and number of activated Ag+/adjuvant+ DCs in the draining lymph nodes (LN) as that of protective H1/CAF01 immunization. Thus, targeting/activating the same DC population by Ag and adjuvant is not sufficient to elicit Th1/Th17 responses. To identify the determinants of Th1/Th17 adjuvanticity, in vivo tracking experiments using fluorescently labeled Ag and adjuvant identified that a separate same-site administration elicits an additional early Ag+/adjuvant− DC population with a nonactivated phenotype, resulting from the earlier targeting of LN DCs by H1 than by CAF01 molecules. This asynchronous targeting pattern was mimicked by the injection of free H1 prior to or with, but not after, H1/CAF01 or H1/CpG/ aluminum hydroxide immunization. The injection of soluble OVA similarly prevented the induction of Th1 responses by OVA/CAF01. Using adoptively transferred OT-2 cells, we show that the Ag targeting of LN DCs prior to their activation generates nonactivated Ag-pulsed DCs that recruit Ag-specific T cells, trigger their initial proliferation, but interfere with Th1 induction in a dose-dependent manner. Thus, the synchronization of DC targeting and activation is a critical determinant for Th1/Th17 adjuvanticity.

Enhancement of Adaptive Immunity by the Human Vaccine Adjuvant AS01 Depends on Activated Dendritic Cells

“…The rapid activation of DCs at a stage when the Ag was most readily available to be endocytosed (i.e., soon after immunization) may be an additional key factor in establishing a strong T cell response. This is suggested by Kamath et al (40) who recently demonstrated that, in the converse situation, the early recruitment of nonactivated Ag-loaded APCs with in the dLN may be detrimental for Th1 responses. Given that high adaptive responses were achieved even when Ag was injected hours after AS01, our study shows that high adaptive responses can be associated with a rapid induction of inflammation and APC activation and may not require a physical association between adjuvant and Ag.…”

Low Antigen Dose in Adjuvant-Based Vaccination Selectively Induces CD4 T Cells with Enhanced Functional Avidity and Protective Efficacy

“…Because no increase in activation-induced cell death or viability after stimulation was observed, it could be speculated that higher vaccine doses led to free Ag not bound by liposome-based CAF. Free Ag drains faster to the draining lymph node and is processed and presented by nonactivated DCs, in turn inducing tolerized or even inhibitory regulatory Ag-specific T cells (44). In fact, the 50-nmol PCLUS6.1-P18 vaccine dose equals ∼1.2 mg/ml, and for a similar liposomal adjuvant (CAF01), concentrations .…”

Novel Injectable Pentablock Copolymer Based Thermoresponsive Hydrogels for Sustained Release Vaccines

“…A particulate carrier loaded with the vaccine antigen and adjuvants was incorporated into the formulation in order to mimic the presence of pathogens and to facilitate synchronous uptake of the vaccine components by APCs (7,8). PLGA-NP were chosen due to their biocompatibility, stability, and versatility.…”

“…Additionally, particulate carriers may facilitate the synchronous presentation of vaccine antigens and adjuvants to dendritic cells, decreasing the potential for the development of tolerogenic immune response (7). Poly lactic-co-glycolic acid nanoparticles (PLGA-NP) have been extensively studied for vaccine delivery and have been reported to target dendritic cells naturally through phagocytosis with efficient delivery of the vaccine components (8).…”