Rewiring human cellular input-output using modular extracellular sensors

Nat Chem Biol. 2017 Feb;13(2):202-209. doi: 10.1038/nchembio.2253. Epub 2016 Dec 12.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antibodies / immunology*
  • Biosensing Techniques*
  • Humans
  • Interleukin-2 / biosynthesis
  • Interleukin-2 / immunology
  • T-Lymphocytes / immunology*
  • Transcription Factors / immunology*
  • Vascular Endothelial Growth Factor A / immunology

Substances

  • Antibodies
  • Interleukin-2
  • Transcription Factors
  • Vascular Endothelial Growth Factor A