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  1. Home
  3. Transcription Factor Collaboration Enables Precise T Cell State Engineering.
  1. Home
  3. Transcription Factor Collaboration Enables Precise T Cell State Engineering.

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Transcription factor collaboration enables precise T cell state engineering.

Rachel E Savage1,2, Christian D McRoberts Amador3,4, Conrad T Hock1,2

  • 1Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138.

Biorxiv : the Preprint Server for Biology
|May 4, 2026

View abstract on PubMed

Summary
This summary is machine-generated.

Researchers identified key transcription factors (TFs) that control CD8+ T cell exhaustion. They discovered RUNX factors collaborate extensively, with RUNX2 and KLF2 interaction driving exhaustion and impacting CAR-T therapy response.

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Area of Science:

  • Immunology
  • Molecular Biology
  • Systems Biology

Background:

  • Transcription factors (TFs) orchestrate gene expression programs crucial for cell fate determination.
  • CD8+ T cell exhaustion, a state of dysfunction, impairs immunity during chronic infections and cancer.
  • Understanding TF collaboration is vital for deciphering cell state regulation.

Purpose of the Study:

  • To identify cell state-specific TFs regulating CD8+ T cell exhaustion.
  • To map TF-program connections and understand their collaborative roles.
  • To explore the potential of TF engineering for therapeutic applications.

Main Methods:

  • Pooled overexpression screens of 3,548 TF and TF isoforms in primary T cells.
  • Perturb-seq (perturb-SHARE-seq) to link TF perturbations to chromatin accessibility and gene expression in single cells.
  • Deep learning framework (seq2PRINT) to predict functional TF interactions.

    • Main Results:

    • Identified 82 regulators collaborating with exhaustion-specific programs.
    • Mapped 12,616 TF-program connections across CD8+ T cell states.
    • Discovered RUNX as a master collaborator, with a specific RUNX2:KLF2 interaction driving exhaustion.
    • Nominated KLF2 as a predictor of CAR-T therapy response.

    Conclusions:

    • The collaborative action of RUNX TFs significantly drives CD8+ T cell states.
    • Targeting TF interactions, like RUNX2:KLF2, can modulate T cell exhaustion.
    • TF tethering offers a strategy for engineering cell identity in cell and gene therapies.