Innate immunity and adjuvants

Abstract

Innate immunity was for a long time considered to be non-specific because the major function of this system is to digest pathogens and present antigens to the cells involved in acquired immunity. However, recent studies have shown that innate immunity is not non-specific, but is instead sufficiently specific to discriminate self from pathogens through evolutionarily conserved receptors, designated Toll-like receptors (TLRs). Indeed, innate immunity has a crucial role in early host defence against invading pathogens. Furthermore, TLRs were found to act as adjuvant receptors that create a bridge between innate and adaptive immunity, and to have important roles in the induction of adaptive immunity. This paradigm shift is now changing our thinking on the pathogenesis and treatment of infectious, immune and allergic diseases, as well as cancers. Besides TLRs, recent findings have revealed the presence of a cytosolic detector system for invading pathogens. I will review the mechanisms of pathogen recognition by TLRs and cytoplasmic receptors, and then discuss the roles of these receptors in the development of adaptive immunity in response to viral infection.

Figure 1.

Interactions of innate and adaptive immunity. When pathogens invade the body, the innate immune system is activated first and participates in the initial attack against the pathogens. Among the cells involved in innate immunity, dendritic cells act as antigen-presenting cells and migrate from the infected tissue to the regional lymph nodes where they present the antigens to T cells. Subsequently, the adaptive immune system is activated, and antibody production and killer T cells are induced. The resulting antibodies and killer T cells specifically attack the pathogens.

Figure 2.

TLR ligands and signalling. TLR receptors recognize different microbial components: the heterodimer of TLR4 and MD-2 recognizes lipopolysaccharide (LPS); TLR2 recognizes triacyl and diacyl portions of lipoproteins together with TLR1 or TLR6, respectively; TLR5 recognizes flagellin, a major component of flagella; TLR3 recognizes double-stranded RNA; TLR7 recognizes single-stranded RNA and TLR9 recognizes bacterial and viral DNA, the so-called CpG DNA. The signalling pathways of TLRs are mediated by selective usage of adaptor molecules, MyD88, TRIF, TIRAP and TRAM. MyD88 is involved in all TLR signalling except for TLR3. TRIF is involved in TLR3 and TLR4 dependent activation of IRF3 via IKKi/TBK1, resulting in type 1 interferon production. TRAM is responsible for the TLR4-MyD88 dependent pathway involving recruitment of TRIF to the cytoplasmic portion of TLR4. TIRAP is involved in recruiting MyD88 to the cytoplasmic portions of TLR2 and TLR4. TLR7 and TLR9-dependent production of type 1 interferon requires direct interaction of MyD88 and IRF7, which occurs only in plasmacytoid dendritic cells. Nucleic acid-recognizing TLRs (TLR3, TLR7, TLR9) are present in the endosome.

Figure 3.

C-type lectins, RIG-like receptors (RLRs) and NOD-like receptors. C-type lectins (CLRs) recognize carbohydrates on micro-organisms via the carbohydrate-binding domain. Dectin-1, Dectin-2, Mincle and CLEC9A are well studied. For example, Dectin-1 activates the Syk tyrosine kinase via the immunoreceptor tyrosine-based activation motif (ITAM) domain, resulting in production of inflammatory cytokines. RLRs comprise RIG-I and MDA5. RLRs are composed of two N-terminal caspase-recruitment domains (CARDs), a central DEAD box helicase/ATPase domain, and a C-terminal regulatory domain. They are localized in the cytoplasm and recognize the genomic RNA of dsRNA viruses, and dsRNA generated as the replication intermediate of ssRNA viruses. RLRs interact with IPS1 via their CARD domains, resulting in type 1 interferon production through IKKi/TBK1. NLRs are composed of a central nucleotide-binding domain (NOD) and C-terminal leucine-rich repeats (LRRs). The N-terminal portions harbour protein-binding motifs. NODs activate caspase-1, resulting in processing of pro-IL-1β to mature IL-1β.

Figure 4.

Induction of adaptive immunity by influenza viral infection and vaccination. In the case of live influenza viruses, the viruses infect a variety of cells except for plasmacytoid dendritic cells (pDC) and produce RNAs, which are recognized by RIG-I, resulting in type 1 interferon production. pDCs are resistant to infection and phagocytose the viral particle, and RNA is liberated in the phagolysome, which result in activation of TLR7/MyD88-dependent pathway and type 1 interferon production. In the case of inactivated whole virus vaccine, this cannot infect but pDCs engulf the inactivated virus, and subsequent activation of TLR7/MyD88-dependent pathway leads to production of type 1 interferon. This pathway is also essential to induction of adaptive immunity against influenza virus. Split vaccine lacking RNA is not effective in naive persons but can play some role in protection by activating memory B cells in people who have already experienced influenza viral infection.