Atlas-guided discovery of transcription factors for T cell programming - PubMed
3 months ago
- #transcription factors
- #T cell programming
- #immunotherapy
- CD8+ T cells differentiate into diverse states impacting immune responses in cancer and chronic infection.
- A comprehensive atlas integrating transcriptional and epigenetic data across nine CD8+ T cell states was built to infer TF activity profiles.
- The study focused on two critical T cell states: terminally exhausted T (TEXterm) cells and tissue-resident memory T (TRM) cells.
- Global TF community analysis revealed distinct pathways and networks underlying protective (TRM) versus dysfunctional (TEXterm) states.
- In vivo CRISPR screening with single-cell RNA sequencing identified TFs governing TEXterm cell differentiation.
- HIC1 and GFI1 were identified as shared regulators of TEXterm and TRM cell differentiation, while KLF6 uniquely regulates TRM cells.
- New TEXterm-selective TFs, ZSCAN20 and JDP2, were discovered with no prior known function in T cells.
- Targeted deletion of ZSCAN20 and JDP2 enhanced tumor control and synergized with immune checkpoint blockade without affecting TRM cell formation.
- Depletion of these TFs in human T cells reduced inhibitory receptor expression and improved effector function.
- The platform enables precise engineering of T cell states for more effective cellular immunotherapies.