Abstract
The immune system is a sophisticated network of different cell types performing complex biocomputation at single-cell and consortium levels. The ability to reprogram such an interconnected multicellular system holds enormous promise in treating various diseases, as exemplified by the use of chimeric antigen receptor (CAR) T cells as cancer therapy. However, most CAR designs lack computation features and cannot reprogram multiple immune cell types in a coordinated manner. Here, leveraging our split, universal, and programmable (SUPRA) CAR system, we develop an inhibitory feature, achieving a three-input logic, and demonstrate that this programmable system is functional in diverse adaptive and innate immune cells. We also create an inducible multi-cellular NIMPLY circuit, kill switch, and a synthetic intercellular communication channel. Our work highlights that a simple split CAR design can generate diverse and complex phenotypes and provide a foundation for engineering an immune cell consortium with user-defined functionalities.
Highlights
The immune system is a sophisticated network of different cell types performing complex biocomputation at single-cell and consortium levels
Since conventional chimeric antigen receptor (CAR) are functional in many immune cell types, we tested whether the SUPRA CAR system can redirect antigen specificity in various T-cell subtypes, Natural Killer (NK) cell, and macrophage
We will focus on evaluating the induciblity and logic operation of the SUPRA CAR system by measuring population-level cell killing for cytotoxic cells and cytokine production for other immune cells
Summary
The immune system is a sophisticated network of different cell types performing complex biocomputation at single-cell and consortium levels. The ability to engineer distributed processing and cell–cell communication between human immune cells could lead to the development of synthetic immune cell consortia, which could further improve the safety and efficacy of cellular immunotherapy Such a synthetic approach would provide insights into the governing principles of biocomputation in human immune cells. The orthogonal SUPRA CARs can independently control different T-cell subsets These functions highlight a powerful design feature afforded by the split CAR framework—namely, a collection of orthogonal split CARs controlling different signaling domains and/or expressed in different cell types can achieve complex biocomputation at the single-cell level and consortium level
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