Immunologic Adjuvant - Adjuvants and Toll-like Receptors

Adjuvants and Toll-like Receptors

The ability of immune system to recognize molecules that are broadly shared by pathogens is, in part, due to the presence of special Immune receptors called TLRs that are expressed on leukocyte membranes. TLRs were first discovered in drosophila, and are membrane bound pattern recognition receptors (PRRs) responsible for detecting most (although certainly not all) antigen-mediated infections. In fact, some studies have shown that in the absence of TLR, leukocytes become unresponsive (no inflammatory responses) to some microbial components such as LPS. There are at least thirteen different forms of TLR, each with its own characteristic ligand. Prevailing TLR ligands described to date (all of which elicit adjuvant effects) include many evolutionarily conserved molecules such as LPS, lipoproteins, lipopeptides, flagellin, double-stranded RNA, unmethylated CpG islands and various other forms of DNA and RNA classically released by bacteria and viruses.

The binding of ligand - either in the form of adjuvant used in vaccinations or in the form of invasive moieties during times of natural infection - to the TLR marks the key molecular events that ultimately lead to innate immune responses and the development of antigen-specific acquired immunity. The very fact that TLR activation leads to adaptive immune responses to foreign entities explains why so many adjuvants used today in vaccinations are developed to mimic TLR ligands. So far, single ligands have been used as vaccine adjuvants. However, studies in 2006 and 2011 suggest that the combination of more than one adjuvant with either an interferon or an interleukin could produce a synergistic enhancement of immune response.

It is believed that upon activation, TLRs recruit adapter proteins (proteins that mediate other protein-protein interactions) within the cytosol of the immune cell in order to propagation the antigen-induced signal transduction pathway. To date, four adapter proteins have been well-characterized. These proteins are known as MyD88, Trif, Tram and TIRAP (also called Mal). These recruited proteins are then responsible for the subsequent activation of other downstream proteins, including protein kinases (IKKi, IRAK1, IRAK4, and TBK1) that further amplify the signal and ultimately lead to the upregulation or suppression of genes that orchestrate inflammatory responses and other transcriptional events. Some of these events lead to cytokine production, proliferation, and survival, while others lead to greater adaptive immunity. The high sensitivity of TLR for microbial ligands is what makes adjuvants that mimic TLR ligands such a prime candidate for enhancing the overall effects of antigen specific vaccinations on immunological memory.

Finally, the expression of TLRs is vast as they are found on the cell membranes of innate immune cells (DCs, macrophages, natural killer cells), cells of the adaptive immunity (T and B lymphocytes) and non immune cells (epithelial and endothelial cells, fibroblasts).

This further substantiates the importance of administering vaccines with adjuvants in the form of TLR ligands, as they will be capable of eliciting their positive effects across the entire spectrum of innate and adaptive immunity. Nevertheless, there are adjuvants whose immune-stimulatory function completely bypasses the TLR signaling pathway. While all TLR ligands are adjuvants, not all adjuvants are TLR ligands.