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Versa) Understanding of TLR Signaling (And Vice Impacted Our How Discovery of Toll-Mediated Innate Immunity in Drosophila Impacted Our Understanding of TLR Signaling (and Vice Versa) This information is current as of September 24, 2021. Stefanie N. Vogel J Immunol 2012; 188:5207-5209; ; doi: 10.4049/jimmunol.1201050 http://www.jimmunol.org/content/188/11/5207 Downloaded from References This article cites 34 articles, 16 of which you can access for free at: http://www.jimmunol.org/content/188/11/5207.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 24, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. How Discovery of Toll-Mediated Innate Immunity in Drosophila Impacted Our Understanding of TLR Signaling (and Vice Versa) Stefanie N. Vogel was delighted when The Journal of Immunology invited its body (Fig. 5 in Ref. 1) is undoubtedly the most widely me to write a Pillars of Immunology article on one of my reproduced figure shown in innate immunity lectures today! I favorite papers, the 1996 publication titled, “The Dor- The implications of this paper were far-reaching in that it soventral Regulatory Gene Cassette spa¨tzle/Toll/cactus Con- impacted the discovery of mammalian TLRs by providing trols the Potent Antifungal Response in Drosophila Adults” the first direct evidence that resistance to infection was the Downloaded from by Bruno Lemaitre et al. (1). In this seminal publication, the consequence of inducible expression of antimicrobial genes authors deftly combined genetic, biochemical, and molecular secondary to activation of the Toll NF-kB–like signaling approaches to reveal that the Toll signaling pathway, origi- pathway. The significance of this work was acknowledged nally recognized to regulate dorsoventral patterning in Dro- recently by naming the senior author, Jules Hoffmann, as sophila embryos by activating an NF-kB–like Rel protein corecipient of one half of the 2011 Nobel Prize in Physiology (recently reviewed in Ref. 2), was also responsible for tran- or Medicine. http://www.jimmunol.org/ scriptional activation of the gene that encodes Drosomysin, In a 2004 review, Lemaitre (3) provided a timeline of key an antifungal peptide. Using adult flies with gain-of-function observations in both insect and mammalian immunology or loss-of-function mutations in genes shown previously to that resulted in a convergence of ideas, leading first to their contribute to induction of both the antifungal peptide Droso- landmark publication and ultimately to the discovery of mycin and antibacterial peptides, Lemaitre et al. found the mammalian TLRs. Notably, the identification of inducible following: (1) The embryonic signaling pathway comprising antibacterial peptides in insects (4) and mammals (5), coupled gene products between spz and cact, and not upstream or with the finding that genes encoding antibacterial Attacin downstream genes—that is, genes constituting the Toll signal- peptides contained NF-kB–like binding sites in their pro- by guest on September 24, 2021 ing “cassette”—was necessary for the antifungal response in moters (6), pointed to a signaling pathway in insects that adult flies; (2) although this same pathway contributes par- was homologous to known immune signaling pathways lead- tially to the induction of antibacterial gene expression (includ- ing to NF-kB translocation in mammals. However, in 1991, ing genes encoding Cecropins, Attacin, and insect Defensin), Gay and Keith (7) and Schneider et al. (8) independently an additional pathway regulated by a distinct locus, imd, was reported a significant degree of homology between the also necessary for antibacterial peptide gene expression; (3) cytoplasmic domains of Drosophila Toll protein and the expression of other antibacterial peptide genes, Diptercin and human IL-1R. Gay and Keith found that this homology ex- Drosocin, is regulated by the imd signaling pathway, apparently tended for 135 aa with identical or conservative substitutions without cross-talk from the Toll signaling pathway; and (4) at 45% of positions (now known as the Toll/IL-1R/resistance finally, and most importantly, adult flies with mutations in the [TIR] domain). Consistent with this finding, Heguy et al. (9) Toll signaling pathway succumb to infection with the fungus described a 50-aa subregion within the TIR domain that was Aspergillus fumigatus, but not the bacterium Escherichia coli, essential for IL-1–mediated activity. When coupled with the and conversely, flies with defects in imd failed to survive E. coli 1988 observation by van der Meer et al. (10) that a low dose infection owing to uncontrolled bacterial replication, yet re- of IL-1 protected granulocytopenic mice from lethal Gram- sisted infection with A. fumigatus. Flies with mutations in both negative infection, it is clear that the idea of TIR domain- pathways failed to survive fungal or bacterial challenge. The mediated “nonspecific” host immunity was actually already image of the dead adult fly with fungal hyphae extending from established for mammals in the early 1990s. That NF-kB translocation to the nucleus was observed in IL-1–treated cells and paralleled the signal transduction events Department of Microbiology and Immunology, University of Maryland School of mediated by Drosophila Toll upon activation by its endog- Medicine, Baltimore, MD 21201 enous ligand, spa¨tzle,provided further support for the idea S.N.V. is supported by National Institutes of Health Grant R01AI018797. that parallel signaling pathways leading to NF-kBtrans- Address correspondence and reprint requests to Dr. Stefanie N. Vogel, University location might regulate induction of innate immune response of Maryland, 685 West Baltimore Street, HSF1 Suite 380, Baltimore, MD 21201. genes in both insects and higher species. Between 1993 and E-mail address: [email protected] 1995, multiple studies in Drosophila provided evidence for an Abbreviation used in this article: TIR, Toll/IL-1R/resistance. additional, nondevelopmental role for Toll in insect immu- Copyright Ó 2012 by The American Association of Immunologists, Inc. 0022-1767/12/$16.00 nity (11–15), culminating in a series of papers by Lemaitre www.jimmunol.org/cgi/doi/10.4049/jimmunol.1201050 5208 PILLARS OF IMMUNOLOGY et al. (16, 17), including their 1996 Cell paper showing that Although many laboratories attempted to clone the Lps gene mutations in Toll and imd in vivo resulted in increased sus- by various approaches (reviewed in Refs. 22 and 23), Bruce ceptibility to infection in Drosophila (1). Beutler and colleagues (29) were successful using a positional The idea of the existence of cellular receptors that could cloning approach to clone the murine TLR4 gene. This sense pathogens and deliver “danger” signals to cells was put achievement was followed by a landmark paper by Poltorak forward in 1989 by the late Charles Janeway (18). He pro- et al. (30), published in December 1998, showing that the posed that such receptors on mammalian APCs would not C3H/HeJ mouse strain carried a point mutation in the TIR only recognize conserved pathogenic structures but also signal domain of Tlr4 and that Tlr4 was largely deleted in the intracellularly, leading to the transcriptional upregulation of C57BL/10ScCr strain. For this discovery, Dr. Beutler was Dr. costimulatory molecules based, in part, on the observation Hoffmann’s corecipient of the 2011 Nobel Prize that was also that “a whole variety of microbial substances could stimulate shared with Dr. Ralph Steinman for his pioneering work on the antigen-presenting cells to express what we believed to dendritic cells. be costimulatory activity” (19). In 1997, Ruslan Medzhitov, An avalanche of studies in mammalian innate immunity while working with Dr. Janeway, cloned “hToll” (later identi- soon ensued. Within a few months after Poltorak et al. (30) fied as human TLR4) (20). Because these investigators did not published their findings, independent confirmation was pro- know the nature of the ligand for hToll, or if there existed vided by Malo and colleagues (31), followed in short order by a spa¨tzle homolog in mammals, they engineered a construct work from Shizuo Akira’s laboratory (32) showing that mice 2/2 that encoded the CD4 ectodomain with the TLR4 intracellular with a targeted mutation in TLR4 (i.e., TLR4 mice) both Downloaded from domain. This would have allowed them to cross-link the CD4 were unresponsive to LPS and exhibited increased suscepti- ectodomains with anti-CD4 Ab, if necessary. When this CD4– bility to infection. Kawai et al. (33) soon reported that 2 2 hToll fusion protein was overexpressed in mammalian cells, MyD88 / mice were refractory to lethal challenge with LPS 2 2 however, it constitutively activated NF-kB and resulted in the in vivo and that MyD88 / macrophages responded poorly upregulation of costimulatory molecules, as originally pre- to LPS to express NF-kB–dependent cytokine genes. This dicted by Janeway. This work, published just 1 y after Lemaitre observation was key because MyD88, the functional ho- http://www.jimmunol.org/ et al. (1), represents the first direct link between TLR signaling in molog of Drosophila MyD88 (dMyD88), served as a critical mammalian cells that leads to NF-kB activation, that in turn, adapter protein for both IL-1R and TLRs (reviewed in upregulates the costimulatory molecules, and thereby facilitates Ref.
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