The Advent of Toll-like Receptors
In the mid-1980s, the Toll protein of the fruit fly, Drosophila melanogaster, was first described.2 In Drosophila, Toll controls, among other things, the release of peptides that are active against infectious agents, a major
line of defense.3 In subsequent years, a related set of Toll-like receptors (TLRs) were found on or in mammalian APCs, including dendritic
cells, macrophages, endothelial cells, and some plasmacytoid cells.4 Together with neutrophils, eosinophils, basophils, and mast cells, these constitute the "innate immune system." These cells
mount the first attack against incoming pathogens, resulting in an inflammatory response that is the necessary predecessor
of the T-cell and B-cell "adaptive immune response."
In 1997, Medzhitov, Janeway, and others demonstrated that TLRs are the mediators of the innate immune response.5 TLRs collectively recognize families of structures that are unique to pathogens and not part of mammalian biology. These
structures are collectively termed pathogen-associated molecular patterns (PAMPs), and they provide the primary signal to
the mammalian host that a pathogenic insult has occurred.5 Figure 1 illustrates the known TLRs and their ligands, or PAMPs.6 Each TLR binds a specific class of pathogen-related molecules. For example, TLR4 binds to lipopolysaccharides (LPS) found
on the surface of bacteria but not in the mammalian host.1 TLR3 binds to double-stranded RNA (dsRNA), a non-mammalian nucleic acid conformation that is the genome structure or replication
intermediate of many viruses.1 TLR5 binds to flagellin, a protein that polymerizes to form the bacterial flagella.1 Mammalian TLRs are expressed either on the surface or in an internal compartment inside of an APC. In general, cell surface
TLRs tend to recognize bacterial components (e.g., lipoproteins, lipopolysaccharides, flagellin) whereas internal TLRs tend
to recognize nucleic acids and analogs (e.g., dsRNA, CpG oligonucleotides, or nucleotide derivatives).
Figure 1. The known Toll-like receptors (TLRs) and their ligands. Pathogen-associated molecules are recognized by TLRs.
PAMP and TLR Binding
Binding of a PAMP to a TLR results in a cascade of events inside an APC (Figure 2, unpublished data). First, the PAMP-pathogen
complex binds to a TLR and is internalized to an endocytic vesicle. The vesicle now contains an activated TLR that sends a
series of signals to the nucleus. These signals drive the fusion of the vesicle with a lysosome where the contents are degraded
into peptides for presentation in the groove of the MHC class I or class II complex.5 TLR signaling triggers expression of genes for cytokines, which stimulate neighboring T cells as well as the expression
of co-stimulatory molecules (CD80/86) that bind to the T cell and promote its activation.1 This triad of peptide processing and presentation, cytokine secretion, and T-cell co-stimulation satisfies the criteria
for activating a T cell and initiating a productive immune response.
Figure 2. Toll-like receptors' mechanism of action: the stimulation of Toll-like receptors activates pathways that 1) promote
antigen processing and presentation and 2) provide the second signal to T cells, informing them that the antigens are proper
subjects for vigorous immune response.