TY - JOUR
T1 - Rewiring human cellular input-output using modular extracellular sensors
AU - Schwarz, Kelly A.
AU - Daringer, Nichole M.
AU - Dolberg, Taylor B.
AU - Leonard, Joshua N.
PY - 2017/2/1
Y1 - 2017/2/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85003955384&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85003955384&partnerID=8YFLogxK
U2 - 10.1038/nchembio.2253
DO - 10.1038/nchembio.2253
M3 - Article
C2 - 27941759
AN - SCOPUS:85003955384
SN - 1552-4450
VL - 13
SP - 202
EP - 209
JO - Nature Chemical Biology
JF - Nature Chemical Biology
IS - 2
ER -