title: Rewiring human cellular input-output using modular extracellular sensors.
abstract: Engineered cell-based therapies comprise a promising emerging strategy for treating diverse diseases. Realizing this promise requires new tools for engineering cells to sense and respond to soluble extracellular factors, which provide information about both physiological state and the local environment. Here, we report such a biosensor engineering strategy, leveraging a self-contained receptor-signal transduction system termed modular extracellular sensor architecture (MESA). We developed MESA receptors that enable cells to sense vascular endothelial growth factor (VEGF) and, in response, secrete interleukin 2 (IL-2). By implementing these receptors in human T cells, we created a customized function not observed in nature-an immune cell that responds to a normally immunosuppressive cue (VEGF) by producing an immunostimulatory factor (IL-2). Because this platform utilizes modular, engineerable domains for ligand binding (antibodies) and output (programmable transcription factors based upon Cas9), this approach may be readily extended to novel inputs and outputs. This generalizable approach for rewiring cellular functions could enable both translational applications and fundamental biological research.
authors.affiliation: Department of Chemical and Biological Engineering, Northwestern University, Evanston, Illinois, USA.|Center for Synthetic Biology, Northwestern University, Evanston, Illinois, USA.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Schwarz
authors.affiliation: Department of Chemical and Biological Engineering, Northwestern University, Evanston, Illinois, USA.
authors.forename: Nichole M
authors.initials: NM
authors.lastname: Daringer
authors.affiliation: Department of Chemical and Biological Engineering, Northwestern University, Evanston, Illinois, USA.|Center for Synthetic Biology, Northwestern University, Evanston, Illinois, USA.
authors.forename: Taylor B
authors.initials: TB
authors.lastname: Dolberg
authors.affiliation: Department of Chemical and Biological Engineering, Northwestern University, Evanston, Illinois, USA.|Center for Synthetic Biology, Northwestern University, Evanston, Illinois, USA.|Chemistry of Life Processes Institute, Northwestern University, Evanston, Illinois, USA.|Member, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Evanston, Illinois, USA.
authors.forename: Joshua N
authors.initials: JN
authors.lastname: Leonard
mesh_terms: D000906:Antibodies / Q000276:immunology*; D015374:Biosensing Techniques; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014157:Transcription Factors / Q000276:immunology*; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology
chemical_list: D000906:Antibodies; D007376:Interleukin-2; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A