A cell biological view of toll-like receptor function: regulation through compartmentalization

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A cell biological view of Toll-like receptor function: regulation through compartmentalization
Gregory M. Barton* and Jonathan C. Kagan‡

Abstract | An emerging paradigm in innate immune signalling is that cell biological context can influence the outcome of a ligand–receptor interaction. In this Review we discuss how Toll-like receptor (TLR) activation and signal transduction areregulated by subcellular compartmentalization of receptors and downstream signalling components. In particular, we focus on the functional specialization of TLRs in the endosomal system. We discuss recent studies that illustrate how basic aspects of the cellular machinery contribute to TLR function and regulation. This emerging area of research will provide important information on how immune signaltransduction networks depend on (and in some cases influence) the generic regulators that organize eukaryotic cells.
The past decade has witnessed an incredible expansion in our understanding of the molecular components of innate immunity and their function in host defence1,2. The recognition of microorganisms is mediated by several families of innate immune receptors that collectively survey theextracellular space, endolysosomal compartments and the cytoplasm for signs of infection or tissue damage. These receptors, the specificities of which are fixed in the germline, can recognize diverse pathogenic microorganisms by targeting highly conserved molecular patterns that are common to broad pathogen classes3,4. The Toll-like receptor (TLR) family is the best characterized group of innateimmune receptors in terms of known ligands, downstream signalling pathways and functional relevance. There are 10 human TLR family members, each with distinct ligands and functional properties. As these receptors have a central role in linking pathogen recognition to induction of innate immunity, inflammation and adaptive immunity, there is tremendous interest in understanding how TLR activationis regulated. TLRs recognize a bewildering range of microbial ligands, such as bacterial and fungal cell wall components, bacterial lipoproteins, highly conserved microbial proteins, and bacterial and viral nucleic acids. The molecular basis of such diverse ligand binding remains poorly understood, although the elucidation of several recent structures of ligand–receptor complexes suggest that notall TLRs use the same ligand-binding interface5–7. Recognition of microorganisms is linked to a cascade of events that promote inflammation, activation of innate immune responses and priming of adaptive immune responses. Key to this central role in host defence is the expression of TLRs on antigen-presenting cells, especially macrophages and dendritic cells (DCs)8. When these cells encountermicroorganisms or microbial products, TLR activation initiates signal transduction pathways that culminate in potent transcriptional responses9 (BOX 1). In addition to the induction of distinct signalling pathways, TLRs sample different compartments within cells. The cellular localization of these receptors has important consequences for ligand accessibility and can also affect downstream signallingevents. Certain differences in subcellular localization are stable, whereas others are more dynamic (see below). The TLRs involved in the recognition of nucleic acids (TLR3, TLR7, TLR8 and TLR9) are localized within endolysosomal compartments, whereas other TLR family members (TLR1, TLR2, TLR4, TLR5 and TLR6) are found at the cell surface9. The precise nature of the compartment where intracellularTLRs meet internalized ligands remains poorly defined, and it is likely that features of the compartment differ depending on the composition of the internalized cargo and the cell type under consideration. TLRs that are normally present at the surface can also enter the endocytic pathway following their activation10–12. These receptors are rapidly recruited to phagosomes or endosomes containing...