TLR-mediated innate immune recognition.

Immune recognition has always been one of the main points of interest in immunology. It is well appreciated that there are several distinct strategies of immune recognition that operate in the mammalian immune system. These are traditionally grouped as innate and adaptive, based on the use of either germline-encoded or somatically-generated receptors, respectively. Beyond the genetic nature of the receptors involved, however, the distinction between the two types of immune recognition is not always clear-cut. For example, complement receptors, TLRs, and presumably other types of non-clonal “innate” immune receptors can cooperate with B cell receptors in pathogen recognition, and this involves, at least in some cases, co-recognition by the two types of receptors. In addition, the architecture of antigen receptor complexes bears a striking resemblance to a class of innate immune receptor complexes that signal through ITAM-containing adaptor proteins, such as DAP12. In both cases multi-protein receptor complexes are assembled through ionic interactions between charged residues in the transmembrane regions and signal through similar pathways involving ITAM dependent activation of Syk-72 and ZAP-70. Although the classification of immune recognition into innate and adaptive is useful in many ways, it may obscure the heterogeneity of receptors and mechanisms of innate immune recognition. Indeed, the mammalian innate immune system uses several different classes of receptors, including TLRs, NODs, and NALPS, Dectins, RIG-I and MDA-5 and others [1,2]. Some of the receptors are transmembrane proteins (e.g., TLRs and Dectins), some are secreted (e.g., penthaxins and collectins), and some are intracellular cytoplasmic receptors (e.g., RIG-I/MDA-5, NODs). All these receptors detect conserved microbial structures and function as pattern recognition receptors. However signaling pathways initiated by different classes of receptors are very distinct, as are the immune responses induced by these receptors. Furthermore, in some cases different classes of receptors can be “co-engaged” by a given pathogen, for example, TLR2 and Dectin-1 in fungal recognition, and TLRs and NODs in bacterial recognition. In these cases, recognition and signaling mechanisms may have become coupled in some ways to allow coordinated functioning of different receptor classes. However, other combinations of receptors, for example, Dectin-1 and RIG-I, presumably never co-engage and thus would not be expected to be functionally coupled. Currently our knowledge of the functional and mechanistic links between different pattern recognition receptors is incomplete and would have to be improved in order to understand the full complexity of innate immune recognition. While other classes of pattern recognition receptors continue to be characterized, TLRs enjoyed most of the research attention in the past few years. This issue of Seminars in Immunology contains reviews that summarize the current state of the TLR field. The purpose of this overview, aside from serving as a formal introduction, is to highlight some of the key aspects of TLR biology with the emphasis on some major unresolved questions.