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A human homologue of the Drosophila Toll protein signals activation of adaptive immunity

Abstract

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 vertebrates1. 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 Drosophila2,3,4. 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-κB pathway5,6,7. We show that a constitutively active mutant of human Toll transfected into human cell lines can induce the activation of NF-κB and the expression of NF-κB-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.

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Figure 1: Ancient immune defence systems of plants, insects and vertebrates.
Figure 2: a, Amino-acid sequence of human Toll.
Figure 3: Northern blots of poly(A)+RNA demonstrate predominant expression of hToll in spleen (Sp) and peripheral blood leukocytes(PBL).
Figure 4: Signalling function of hToll.

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Acknowledgements

We thank our colleagues for discussions; P. G. Waterbury for DNA sequencing; S.Ghosh and R. Voll for pB2XLuc plasmid and for helpful suggestions; and J. Flaxenberg for assistance. We acknowledge the Howard Hughes Medical Institute and the NIAID, NIH for support of this work.

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Correspondence to Charles A. Janeway Jr.

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Medzhitov, R., Preston-Hurlburt, P. & Janeway, C. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388, 394–397 (1997). https://doi.org/10.1038/41131

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