Immunology of TLR-independent vaccine adjuvants

Vaccine adjuvants target the innate immune system to enhance the immunogenicity of coadministered antigens. Dendritic cells (DCs) are responsible for antigen uptake and presentation to naïve T cells and represent a key target of adjuvant activity. Adjuvants derived from microbial components, such as Toll-like receptor (TLR) agonists, elicit innate immune receptors expressed by DCs. By contrast, particulate adjuvants, like mineral salts, oil-in-water emulsions, and microparticles, do not activate DCs directly, and their mechanism of action is poorly characterized. In the last two years it has been reported that particulate adjuvants induce chemokine production in accessory cells like macrophages, monocytes, and granulocytes, leading to cell recruitment at injection site followed by the differentiation of monocytes into activated DCs. The NLRP3 inflammasome complex is one of the molecular targets of particulate adjuvants and it is required for alum adjuvanticity. Other TLR-independent adjuvants were found to target DCs directly or by other accessory cells like iNKT or mast cells. These findings highlight that the activation of DCs plays a central role in the mechanism of action of all classes of vaccine adjuvants but can occur by a multitude of different pathways and cellular interactions.