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Reddy, N.R.* ; Maachi, H. ; Xiao, Y.* ; Simic, M.S.* ; Yu, W.* ; Tonai, Y.* ; Cabanillas, D.A.* ; Serrano-Wu, E.* ; Pauerstein, P.T.* ; Tamaki, W.* ; Allen, G.M.* ; Parent, A.V.* ; Hebrok, M. ; Lim, W.A.*

Engineering synthetic suppressor T cells that execute locally targeted immunoprotective programs.

Science 386:eadl4793 (2024)

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	Open Access Green

Closed: Verlagsversion online verfügbar 01/2026

Abstract
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Immune homeostasis requires a balance of inflammatory and suppressive activities. To design cells potentially useful for local immune suppression, we engineered conventional CD4⁺ 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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