Efficient Generation of Functional TCRαβ <sup>+</sup> Cytotoxic T Cells from hiPSCs via Small-Molecule Modulation
cells. Notably, AHR inhibition enhanced T cell development and promoted B lymphopoiesis, revealing shared regulatory pathways in lymphoid lineage specification. We also demonstrate that the Oct4-activating compound OAC1 functions as a weak AHR inhibitor, partially recapitulating the effects of canonical AHR blockers in both cellular and zebrafish AHR reporter systems. Collectively, our findings define key molecular circuits governing human lymphoid differentiation and establish practical strategies to optimize the yield and function of hiPSC-derived cytotoxic T cells. This work advances the development of both universal and autologous hiPSC-derived T cell therapies, offering a path forward even for patient-specific hiPSC lines with suboptimal T cell differentiation potential.
Authors
- Netra K. Kambli
- Marcelo Falchetti (ORCID: https://orcid.org/0000-0002-9438-680X)
- Morgan T. Walcheck (ORCID: https://orcid.org/0000-0002-0095-2197)
- Trista E. North (ORCID: https://orcid.org/0000-0003-1249-563X)
- R. Grant Rowe (ORCID: https://orcid.org/0000-0003-3620-2950)
- Roland Windisch (ORCID: https://orcid.org/0000-0003-1294-5151)
- Zachary LeBlanc (ORCID: https://orcid.org/0000-0002-1662-2846)
- George Q. Daley (ORCID: https://orcid.org/0000-0002-6346-5919)
- Caroline Kubaczka (ORCID: https://orcid.org/0000-0002-7783-6602)
- Thorsten M. Schlaeger (ORCID: https://orcid.org/0000-0002-1599-9908)
- Mohamad Najia (ORCID: https://orcid.org/0000-0002-2558-8846)
- Katie Frenis (ORCID: https://orcid.org/0000-0003-4103-0882)
- Yunliang Zhao
- Kelly Yu
- Sharon Wu
Institutions
- Boston Children's Hospital (US)
- Harvard University (US)
- Harvard Stem Cell Institute (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-04-01
- DOI
- https://doi.org/10.64898/2026.03.31.715684
- Primary Topic
- Pluripotent Stem Cells Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00