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Toll receptor families: structure and function
Seminars in Immunology 16 (2004) 1–2
Editorial
Toll receptor families: structure and function
All living organisms are constantly exposed to microorganisms present in the environment, and coping with the invasion of these organisms into the body. The innate immune system is a first line of such defense. When microorganisms invade into the body, phagocytes such as macrophages, neutrophils, and dendritic cells engulf and kill these organisms. At the same time, these cells recognize conserved motifs in pathogens termed “pathogen-associated molecular patterns (PAMPs).” Toll-like receptors (TLRs) play an essential role in the innate recognition of PAMPS, and in the triggering of adaptive immunity in higher organisms alike. In 1996, insect Toll, initially identified as a receptor essential for dorso-ventral polarity in early development of Drosophila, has been shown to be also essential for anti-fungal immunity. This finding led to identification of Toll-like receptors in mammals. Ten mammalian Toll-like receptors (TLR1–10) have been identified to date. The TLR family is characterized by the presence of an extracellular domain containing leucine-rich repeats (LRR) as well as a cytoplasmic domain (TIR domain) similar to that of the IL-1R family. Each member of the Toll-like receptor family recognizes different pathogen components. They include lipopolysaccharide, lipoproteins, peptidoglycan, CpG DNA, double-stranded RNA, bacterial flagellin. Signaling via TLRs is mediated by intracellular signaling molecules share by IL-1R signaling. Stimulation of IL-1R or TLR triggers a signaling cascade involving myeloid differentiation factor 88 (MyD88), IL-1R-associated kinase (IRAK) and TNFR-associated factor 6 (TRAF6), which then leads to the activation of both the nuclear factor kappa B (NF-B) and MAP kinase signaling pathways. However, gene expression profiles induced by individual TLRs are different from each other, indicating a diversity in the TLR signaling. In fact, recent data have demonstrated that TIR domain-containing adaptors provide specificity of TLR signaling. Takeda and Akira summarize the recent progress in the TLR signaling. Lipopolysaccharide, a membrane constituent of Gramnegative bacteria is one of the most potent immunostimulatory PAMPs, and is a causative agent of endotoxin shock. TLR4 is essential for LPS recognition, but not enough. A secretary molecule called MD-2 is required for the response to LPS and is associated with the extracellular LRR domain of TLR4. Miyake discusses the role of MD-2 in LPS recognition. 1044-5323/$ – see front matter © 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.smim.2003.10.001
Bacterial DNA induces the immune response due to the presence of unmehtylated CpG motifs, whereas CpG motifs are suppressed and often methylated in mammals. CpG DNA is thus recognized as a PAMP. The response to CpG DNA is mediated by TLR9. Different from TLR4 signaling that initiates near the plasma membrane, TLR9 signaling initiates around CpG DNA-containing endosomes. Takeshita et al. discuss the recent progress in CpG DNA-mediated signaling pathway from the endosome. Following recognition of ligands TLRs trigger signaling events that result in initiation of adaptive immune response as well as acute innate responses. TLRs control induction of T cell responses by induction of co-stimulatory molecules in DCs and by induction of IL-6 and other cytokines that allow to overcome the suppressive effect of regulator T cells. Such actions skew resultant T cell response towards Th1 phenotype. Pasare and Medzhitov discuss the role of TLRs as a link between innate and adaptive immunity. DCs play a critical role in activation of T cells as well as shaping of the immune response. DCs are heterogeneous in their phenotype, localization, and function. These DC subsets express distinct patterns of TLRs and differently respond to PAMPs. Reis e Sousa discusses the influence of TLR signaling on DC phenotype and function. Tuberculosis still remains a leading infectious cause of death worldwide. Therefore, it is a very urgent development of effective anti-tuberculosis vaccine. It has been shown that several components of mycobacteria have ability to trigger activation of TLRs. The major immunostimulatory component corresponds to a 19-kDa lipoprotein, and activates the immune cells through TLR2. The TLR activation results in direct anti-microbial activity, induction of cytokine secretion, triggering of dendritic cells maturation, and finally development of a protective Th1-biased T cell response. However, mycobacteria have evolved some strategies to evade the host immune response by modulating TLR activation. Krutzik and Modlin review the role of TLRs in combating mycobacteria. Although Toll study in flies paved the way for the subsequent identification of mammalian Toll-like receptors, only Toll in flies has been associated with innate immunity while other Toll-related molecules are suspected to be involved in development. In contrast, all TLRs appear to be involved in the innate immune response, and not in development. Indeed,
2
Editorial / Seminars in Immunology 16 (2004) 1–2
phylogenetic analysis of Toll-like receptors in Drosophila and humans indicates that Tolls evolved independently in insects and mammals. Furthermore, Drosophila Toll functions in innate immune responses to Gram-positive bacteria and fungi, and endogenous ligand, Spatzle is required for this response. This quite contrasts with mammalian Toll-like receptors, which appear to be activated by direct exposure to pathogen patterns, such as peptidoglycan and lipopolysaccharide. Ferrandon et al. discuss the functional divergence of the vertebrate and invertebrate Toll receptors. Immune and inflammatory responses are extraordinarily complex and dynamic. Traditional approaches, which are by and large reductionist, have obviously limitations in a complete understanding of these responses. However, recent availability of genomic sequences in concert with emerging genomic and proteomic technologies will enable us to in-
tegrate reductionist models into reality. Aderem and Smith discuss system biological approach toward understanding of the initial events triggered upon pathogen recognition. Toll research is now making a rapid progress and expanding in terms of the involvement of TLRs in many aspects of inflammatory and immune responses. I believe the articles in this volume will definitely provide the researchers with latest knowledge on TLRs. S. Akira Department of Host Defense Research Institute for Microbial Diseases Osaka University, 3-1, Yamada-oka Suita, Osaka 565-0871,Japan Tel.: +81-6-6879-8303; fax: +81-6-6879-8305 E-mail address: [email protected]
Editorial
Toll receptor families: structure and function
All living organisms are constantly exposed to microorganisms present in the environment, and coping with the invasion of these organisms into the body. The innate immune system is a first line of such defense. When microorganisms invade into the body, phagocytes such as macrophages, neutrophils, and dendritic cells engulf and kill these organisms. At the same time, these cells recognize conserved motifs in pathogens termed “pathogen-associated molecular patterns (PAMPs).” Toll-like receptors (TLRs) play an essential role in the innate recognition of PAMPS, and in the triggering of adaptive immunity in higher organisms alike. In 1996, insect Toll, initially identified as a receptor essential for dorso-ventral polarity in early development of Drosophila, has been shown to be also essential for anti-fungal immunity. This finding led to identification of Toll-like receptors in mammals. Ten mammalian Toll-like receptors (TLR1–10) have been identified to date. The TLR family is characterized by the presence of an extracellular domain containing leucine-rich repeats (LRR) as well as a cytoplasmic domain (TIR domain) similar to that of the IL-1R family. Each member of the Toll-like receptor family recognizes different pathogen components. They include lipopolysaccharide, lipoproteins, peptidoglycan, CpG DNA, double-stranded RNA, bacterial flagellin. Signaling via TLRs is mediated by intracellular signaling molecules share by IL-1R signaling. Stimulation of IL-1R or TLR triggers a signaling cascade involving myeloid differentiation factor 88 (MyD88), IL-1R-associated kinase (IRAK) and TNFR-associated factor 6 (TRAF6), which then leads to the activation of both the nuclear factor kappa B (NF-B) and MAP kinase signaling pathways. However, gene expression profiles induced by individual TLRs are different from each other, indicating a diversity in the TLR signaling. In fact, recent data have demonstrated that TIR domain-containing adaptors provide specificity of TLR signaling. Takeda and Akira summarize the recent progress in the TLR signaling. Lipopolysaccharide, a membrane constituent of Gramnegative bacteria is one of the most potent immunostimulatory PAMPs, and is a causative agent of endotoxin shock. TLR4 is essential for LPS recognition, but not enough. A secretary molecule called MD-2 is required for the response to LPS and is associated with the extracellular LRR domain of TLR4. Miyake discusses the role of MD-2 in LPS recognition. 1044-5323/$ – see front matter © 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.smim.2003.10.001
Bacterial DNA induces the immune response due to the presence of unmehtylated CpG motifs, whereas CpG motifs are suppressed and often methylated in mammals. CpG DNA is thus recognized as a PAMP. The response to CpG DNA is mediated by TLR9. Different from TLR4 signaling that initiates near the plasma membrane, TLR9 signaling initiates around CpG DNA-containing endosomes. Takeshita et al. discuss the recent progress in CpG DNA-mediated signaling pathway from the endosome. Following recognition of ligands TLRs trigger signaling events that result in initiation of adaptive immune response as well as acute innate responses. TLRs control induction of T cell responses by induction of co-stimulatory molecules in DCs and by induction of IL-6 and other cytokines that allow to overcome the suppressive effect of regulator T cells. Such actions skew resultant T cell response towards Th1 phenotype. Pasare and Medzhitov discuss the role of TLRs as a link between innate and adaptive immunity. DCs play a critical role in activation of T cells as well as shaping of the immune response. DCs are heterogeneous in their phenotype, localization, and function. These DC subsets express distinct patterns of TLRs and differently respond to PAMPs. Reis e Sousa discusses the influence of TLR signaling on DC phenotype and function. Tuberculosis still remains a leading infectious cause of death worldwide. Therefore, it is a very urgent development of effective anti-tuberculosis vaccine. It has been shown that several components of mycobacteria have ability to trigger activation of TLRs. The major immunostimulatory component corresponds to a 19-kDa lipoprotein, and activates the immune cells through TLR2. The TLR activation results in direct anti-microbial activity, induction of cytokine secretion, triggering of dendritic cells maturation, and finally development of a protective Th1-biased T cell response. However, mycobacteria have evolved some strategies to evade the host immune response by modulating TLR activation. Krutzik and Modlin review the role of TLRs in combating mycobacteria. Although Toll study in flies paved the way for the subsequent identification of mammalian Toll-like receptors, only Toll in flies has been associated with innate immunity while other Toll-related molecules are suspected to be involved in development. In contrast, all TLRs appear to be involved in the innate immune response, and not in development. Indeed,
2
Editorial / Seminars in Immunology 16 (2004) 1–2
phylogenetic analysis of Toll-like receptors in Drosophila and humans indicates that Tolls evolved independently in insects and mammals. Furthermore, Drosophila Toll functions in innate immune responses to Gram-positive bacteria and fungi, and endogenous ligand, Spatzle is required for this response. This quite contrasts with mammalian Toll-like receptors, which appear to be activated by direct exposure to pathogen patterns, such as peptidoglycan and lipopolysaccharide. Ferrandon et al. discuss the functional divergence of the vertebrate and invertebrate Toll receptors. Immune and inflammatory responses are extraordinarily complex and dynamic. Traditional approaches, which are by and large reductionist, have obviously limitations in a complete understanding of these responses. However, recent availability of genomic sequences in concert with emerging genomic and proteomic technologies will enable us to in-
tegrate reductionist models into reality. Aderem and Smith discuss system biological approach toward understanding of the initial events triggered upon pathogen recognition. Toll research is now making a rapid progress and expanding in terms of the involvement of TLRs in many aspects of inflammatory and immune responses. I believe the articles in this volume will definitely provide the researchers with latest knowledge on TLRs. S. Akira Department of Host Defense Research Institute for Microbial Diseases Osaka University, 3-1, Yamada-oka Suita, Osaka 565-0871,Japan Tel.: +81-6-6879-8303; fax: +81-6-6879-8305 E-mail address: [email protected]