Engineering synthetic suppressor T cells that execute locally targeted immunoprotective programs
Nishith R. Reddy, Hasna Maachi, Yini Xiao, Milos Simic, Wei Yu, Yurie Tonai, Daniela A. Cabanillas, Ella M Serrano-Wu, Philip T. Pauerstein, Whitney Tamaki, Greg M. Allen, Audrey V. Parent, Matthias Hebrok, Wendell A. Lim
Abstract
T cells with synthetic Notch (synNotch) receptors driving antigen-triggered production of anti-inflammatory payloads. Screening a diverse library of suppression programs, we observed the strongest suppression of cytotoxic T cell attack by the production of both anti-inflammatory factors (interleukin-10, transforming growth factor-β1, programmed death ligand 1) and sinks for proinflammatory cytokines (interleukin-2 receptor subunit CD25). Engineered cells with bespoke regulatory programs protected tissues from immune attack without systemic suppression. Synthetic suppressor T cells protected transplanted beta cell organoids from cytotoxic T cells. They also protected specific tissues from unwanted chimeric antigen receptor (CAR) T cell cross-reaction. Synthetic suppressor T cells are a customizable platform to potentially treat autoimmune diseases, organ rejection, and CAR T cell toxicities with spatial precision.