A human homologue of the Drosophila Toll protein signals activation of adaptive immunity.
Induction of the adaptive immune response depends on the expression of co-stimulatory molecules and cytokines by antigen-presenting cells. The mechanisms that control the initial induction of these signals upon infection are poorly understood. It has been proposed that their expression is controlled by the non-clonal, or innate, component of immunity that preceded in evolution the development of an adaptive immune system in vertebrates. We report here the cloning and characterization of a human homologue of the Drosophila toll protein (Toll) which has been shown to induce the innate immune response in adult Drosophila. Like Drosophila Toll, human Toll is a type I transmembrane protein with an extracellular domain consisting of a leucine-rich repeat (LRR) domain, and a cytoplasmic domain homologous to the cytoplasmic domain of the human interleukin (IL)-1 receptor. Both Drosophila Toll and the IL-1 receptor are known to signal through the NF-kappaB pathway. We show that a constitutively active mutant of human Toll transfected into human cell lines can induce the activation of NF-kappaB and the expression of NF-kappaB-controlled genes for the inflammatory cytokines IL-1, IL-6 and IL-8, as well as the expression of the co-stimulatory molecule B7.1, which is required for the activation of naive T cells.
Medzhitov
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R
Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520-8011, USA.
Preston-Hurlburt
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Janeway
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CA
D000595:Amino Acid Sequence; D000818:Animals; D018122:B7-1 Antigen / Q000096:biosynthesis / Q000235:genetics; D002460:Cell Line; D003001:Cloning, Molecular; D004330:Drosophila; D029721:Drosophila Proteins; D006801:Humans; D007109:Immunity; D019476:Insect Proteins / Q000276:immunology*; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics; D019169:Jurkat Cells; D008562:Membrane Glycoproteins / Q000276:immunology*; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology; D051193:Toll-Like Receptors; D014162:Transfection
D018122:B7-1 Antigen; D029721:Drosophila Proteins; D019476:Insect Proteins; D007378:Interleukins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D016328:NF-kappa B; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins; C068721:Tl protein, Drosophila; D051193:Toll-Like Receptors