Toll-like receptors

Beginning with the physical barrier presented by the epithelium, infectious agents such as viruses and bacteria encounter an array of cellular and molecular countermeasures that evolved within the host to resist them. Host immune responses are of two types, termed innate and adaptive. Immediate defensive responses, which include inflammation, phagocytosis of pathogens, and recruitment of a variety of immune cells, are employed against all classes of microbe, irrespective of prior exposure, and are collectively termed the innate immune response. Innate immunity is evolutionarily ancient, and selected mechanisms are known to be conserved from plants to humans. In contrast, the adaptive immune response is mobilized over a more protracted timescale, is influenced by prior exposure, and, by virtue of antigenspecific receptors generated through somatic DNA recombination within lymphoid clones, is highly specific at the molecular level, often to the point of specificity for a particular microbial species. Adaptive immunity evolved relatively recently and exists only in vertebrates. In mammals, the immune response encompasses the innate and adaptive responses, and, although cross-talk occurs between them, each can be carried out independently by distinct cellular and molecular mechanisms. Both innate and adaptive immune responses depend on distinguishing self from non-self. For the innate response, a family of cellular receptors called Toll-like receptors (TLRs), which recognize molecules unique to microbes, constitutes the primary strategy for self versus nonself discrimination. The study of TLRs as critical innate immune activators began with classical genetic studies that led to the identification of Toll-like receptor 4 (TLR4) as the receptor for lipopolysaccharide (LPS), a structural component of the outer membrane of Gram-negative Primer bacteria. Recognition of a total of 10 human and 12 mouse TLRs and their distinct microbial ligands followed soon after. The family of TLRs is now known to represent the major microbe-sensing system in mammals, detecting molecules derived from viruses, fungi, bacteria, and protozoa. Intracellular NOD-like receptors, receptors of the retinoic acidinducible gene I (RIG-I)-like helicase family, C-type lectin receptors, and a subset of the eIF2a kinases also act as microbe sensors. However, some of these sensing systems display TLR dependence, and none is able to fully compensate for a lack of TLR signaling, a condition that results in severe immune deficiency. Here, we review basic concepts of TLR biology, including the ligands, structural properties, cellular localization, and signaling pathways of these receptors. We discuss physiological responses to TLR activation, collectively termed the inflammatory response, and the connection between TLRs and autoimmune and autoinflammatory disease.