Engineering synthetic suppressor T cells that execute locally targeted immunoprotective programs

Nishith R. Reddy(University of California, San Francisco), Hasna Maachi(University of California, San Francisco), Yini Xiao(University of California, San Francisco), Milos Simic(University of California, San Francisco), Wei Yu(University of California, San Francisco), Yurie Tonai(University of California, San Francisco), Daniela A. Cabanillas(University of California, San Francisco), Ella M Serrano-Wu(University of California, San Francisco), Philip T. Pauerstein(University of California, San Francisco), Whitney Tamaki(University of California, San Francisco), Greg M. Allen(University of California, San Francisco), Audrey V. Parent(University of California, San Francisco), Matthias Hebrok(University of California, San Francisco), Wendell A. Lim(University of California, San Francisco)
Science
December 5, 2024
10.1126/science.adl4793
Cited by 48Open Access
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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.

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