Chimeric receptors for jak-stat signal transduction

摘要

The invention provides a chimeric receptor for cellular activation comprising an extracellular domain capable of binding to a cognate molecule, and a cytokine intracellular domain capable of interacting with a Jak-Stat protein, thereby participating in signal transduction, with the proviso that the cytokine intracellular domain is not naturally associated with the extracellular domain. The present invention harnesses cytokine and growth factor receptor cellular activation pathways for responses to different receptor ligands, thus enabling reconstitution of cellular activation to a ligand, such as a cytokine or growth factor, where some deficiency prevents activation by the native pathway; targeting of effector cells to tumors, virally infected cells, or autoimmune cells; and creating new cytokine or growth factor sensitivities in responder cells, e.g., to develop an assay system in which cells not normally responsive to a given cytokine are rendered responsive. In specific embodiments, the cytokine intracellular domain interacts with a Jak protein selected from the group consisting of Jak1, Jak2, Jak3, and Tyk2. In another embodiment, preferably the cytokine intracellular domain interacts with a Stat protein selected from the group consisting of Stat1 alpha , Stat1 beta , Stat2, Stat3, Stat4, Stat5 and Stat6. In specific examples, various functional chimeric constructs, including gamma R2/ gamma R1, gamma R2/ alpha R1, gamma R2/ alpha R2, gamma R2/CRF, gamma R2/ gamma C, IL-10R/ gamma R1, EpoR/ gamma R1, EpoR/ gamma R2, gamma R1/EpoR, gamma R2/EpoR, H1/ gamma R1, and L1/ gamma R2, were prepared.