Over the last decades, vaccine development has advanced significantly in pursuing higher safety with less side effects. However, this is often accompanied by a reduction in vaccine immunogenicity and an increased dependency on adjuvants to enhance vaccine potency. Especially for diseases like cancer, it is important that therapeutic vaccines contain adjuvants that promote strong T cell responses. An important mode of action for such adjuvants is to prolong antigen exposure to dendritic cells (DCs) and to induce their maturation. These mature DCs are extremely effective in the activation of antigen-specific T cells, which is a pre-requisite for induction of potent and long-lasting cellular immunity. For the activation of CD8+ cytotoxic T cell responses, however, the exogenous vaccine antigens need to gain access to the endogenous MHCI presentation pathway of DCs, a process referred to as antigen cross-presentation. In this review, we will focus on recent insights in clinically relevant vaccine adjuvants that impact DC cross-presentation efficiency, including aluminum-based nanoparticles, saponin-based adjuvants, and Toll-like receptor ligands. Furthermore, we will discuss the importance of adjuvant combinations and highlight new developments in cancer vaccines. Understanding the mode of action of adjuvants in general and on antigen cross-presentation in DCs in particular will be important for the design of novel adjuvants as part of vaccines able to induce strong cellular immunity.
Saponin-based adjuvants (SBAs) are promising new adjuvants that stand out as they not only enforce CD4 + T cell-mediated immunity and antibody responses, but also induce an unprecedented level of antigen cross-presentation by dendritic cells (DC) and subsequent CD8 + T cell activation. We discovered that SBA’s ability to boost cross-presentation depends on the induction of lipid bodies (LBs). Moreover, the MHCIIloCD11bhi DC subset was identified to be most responsive to SBA-induced cross-presentation. The aim is to further unravel the mechanisms behind the induction of DC cross-presentation by SBAs. Here we show that SBAs specifically induce the PKR-like Endoplasmic Reticulum kinase (PERK) pathway and that SBA-induced DC cross-presentation is dependent on activation of the PERK pathway. PERK activation and LB formation are both crucial for SBA-induced cross-presentation and PERK inhibition has little or no effect on SBA-induced LB formation. SBA’s responsiveness, LB formation and PERK activation are specific for the MHCIIloCD11bhi DCs. These findings contribute to understanding the pathways involved in SBA-induced cross-presentation and immune activation which will ultimately lead to the development of vaccines with improved efficiency and safety.
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