Medzhitov R, Preston-Hurlburt P, Janeway C A
Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520-8011, USA.
Nature. 1997 Jul 24;388(6640):394-7. doi: 10.1038/41131.
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.
适应性免疫反应的诱导依赖于抗原呈递细胞上共刺激分子和细胞因子的表达。感染时控制这些信号初始诱导的机制仍知之甚少。有人提出，它们的表达受免疫的非克隆性或先天性成分控制，这种成分在脊椎动物适应性免疫系统发育之前就已在进化中存在。我们在此报告果蝇Toll蛋白（Toll）的人类同源物的克隆和特性，该蛋白已被证明可在成年果蝇中诱导先天性免疫反应。与果蝇Toll一样，人类Toll是一种I型跨膜蛋白，其细胞外结构域由富含亮氨酸的重复序列（LRR）结构域组成，细胞质结构域与人白细胞介素（IL）-1受体的细胞质结构域同源。已知果蝇Toll和IL-1受体均通过NF-κB途径发出信号。我们表明，转染到人细胞系中的组成型活性人类Toll突变体可诱导NF-κB的激活以及炎症细胞因子IL-1、IL-6和IL-8的NF-κB控制基因的表达，以及共刺激分子B7.1的表达，而B7.1是激活初始T细胞所必需的。
