A HUMAN HOMOLOG 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. T he mechanisms that control the initial induction of these signals upon infection are poorly understood. It has been proposed that their expr ession is controlled by the non-clonal, or innate, component of immuni ty that preceded in evolution the development of an adaptive immune sy stem in vertebrates(1). We report here the cloning and characterizatio n of a human homologue of the Drosophila toll protein (Toll) which has been shown to induce the innate immune response in adult Drosophila(2 -4). Like Drosophila Toll, human Toll is a type I transmembrane protei n with an extracellular domain consisting of a leucine-rich repeat (LR R) domain, and a cytoplasmic domain homologous to the cytoplasmic doma in of the human interleukin (IL)-1 receptor. Both Drosophila Toll and the IL-1 receptor are known to signal through the NF-kappa B pathway(5 -7). We show that a constitutively active mutant of human Toll transfe cted into human cell lines can induce the activation of NF-kappa B and the expression of NF-kappa B-controlled genes for the inflammatory cy tokines IL-1, IL-6 and IL-8, as well as the expression of the co-stimu latory molecule B7.1, which is required for the activation of naive T cells.