Atlas-Guided Discovery of Transcription Factors for T Cell Programming

Area of Science:

• Immunology and Molecular Biology: Focuses on T cell differentiation and the role of transcription factors in immune responses.

Background:

• Transcription factors (TFs) are crucial regulators of T cell differentiation into specialized states.
• Understanding TF activity is key to programming T cells for therapeutic applications in cancer and viral infections.

Purpose of the Study:

• To create a comprehensive atlas of TF activity across nine CD8+ T cell differentiation states.
• To identify and validate specific TFs that drive terminally exhausted (TEXterm) and tissue-resident memory (T_RM) T cell fates.
• To leverage TF insights for engineering improved T cell therapies.

Main Methods:

• Generation of a transcriptional and epigenetic atlas of CD8+ T cell differentiation states.
• In vivo CRISPR screening coupled with single-cell RNA sequencing (Perturb-seq) for TF activity validation.
• Global TF community analysis to understand regulatory networks.

Main Results:

• Catalogued TF activity fingerprints for distinct T cell states, revealing novel regulatory mechanisms.
• Identified and validated novel TEXterm-specific TFs (e.g., ZSCAN20, JDP2, ZFP324) whose deletion enhances anti-tumor immunity.
• Discovered multi-state TFs (e.g., HIC1, GFI1) important for both TEXterm and T_RM states.
• Uncovered pathways like protein catabolism linked to TEXterm differentiation.

Conclusions:

• The developed TF atlas and prediction platform enable precise engineering of T cell states for enhanced immunotherapy.
• Targeting identified TEXterm-specific TFs improves tumor control and synergizes with immune checkpoint blockade.
• This work provides critical insights into the molecular mechanisms distinguishing functional T cell states.