Toll-like receptors and their signaling mechanism in innate immunity

In Drosophila the Toll family, a group of transmembrane proteins, plays crucial roles in the host defense against invading pathogens. Mammalian species also conserve this system as the Toll-like receptor (TLR) family, which includes more than 10 members that have been identified so far. Both the Toll and TLR families recognize various kinds of microorganisms through pathogen-associated molecular patterns. Mammalian TLRs are expressed on macrophages and dendritic cells and mediate the signal for cytokine release or upregulation of costimulatory molecules. These activities cooperatively generate host defense mechanisms. Recently, gene targeting experiments, including ours, have contributed much to clarifying not only the function but also the signaling mechanism of TLRs. TLR2 is essential for recognizing lipopeptides and lipoproteins from several microorganisms and also peptidoglycans derived from gram-positive bacteria. TLR4 recognizes lipopolysaccharides and lipoteichoic acids from gram-negative and- positive bacteria, respectively. Furthermore, TLR9 is critical for recognizing bacterial DNAs. Thus, TLRs distinguish various immunostimulatory molecular patterns. Although TLR9 can produce similar biological responses, studies with mutant mice lacking a TLR-associating protein, MyD88, showed that TLR signaling is differentially regulated among TLR family members. Here, we describe recent progress in elucidating the function and signaling mechanisms of the TLR family.