Design of soluble Notch agonists that drive T cell development and boost immunity
- PMID: 40752493
- PMCID: PMC12327808
- DOI: 10.1016/j.cell.2025.07.009
Design of soluble Notch agonists that drive T cell development and boost immunity
Abstract
The rational design of receptor agonists to control cell signaling is an emerging strategy for developing disease therapeutics. Creating a soluble cytokine-like agonist for the Notch receptor, which regulates cell fate in embryonic and adult development, is challenging, as receptor activation requires a mechanical force that is usually mediated by cell-associated transmembrane ligands. Here, we exploit computationally designed protein complexes with precise valencies and geometries to generate soluble cytokine-like Notch agonists. These molecules promote cell-cell bridging, cluster Notch receptors at cell synapses, and activate receptor signaling. We show that these agonists drive T cell differentiation from cord blood progenitors and human induced pluripotent stem cells (iPSCs) and in bioreactor production of T cells in liquid suspension. When delivered intravenously in mice, they stimulate cytokine production, expansion of antigen-specific CD4+ T cells, and antibody class switching. These de-novo-designed ligands can be broadly applied to optimize in vitro cell differentiation and advance immunotherapy development.
Keywords: Notch signaling; T cell development; T cell immunity; computational protein design; iPSC-derived T cells; immunotherapy; protein agonist; soluble Notch activation; vaccine.
Copyright © 2025 Elsevier Inc. All rights reserved.
Conflict of interest statement
Declaration of interests R.M., R.J., E.D.E., D.B., S.C.B., and G.Q.D. filed patents related to C3-DLL4 soluble Notch agonist. R.M. and G.Q.D. filed patents related to C5(15H)-DLL4 soluble Notch agonist. G.Q.D. is an advisory board member at Cell.
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