In vivo CRISPR screening identifies Fli1 as a transcriptional safeguard that restrains effector CD8 T cell differentiation during infection and cancer
Chen, Z.; Arai, E.; Khan, O.; Zhang, Z.; Ngiow, S. F.; He, Y.; Huang, H.; Manne, S.; Cao, Z.; Baxter, A. E.; Cai, Z.; Freilich, E.; Ali, M. A.; Giles, J. R.; Wu, J. E.; Greenplate, A. R.; Kurachi, M.; Nzingha, K.; Ekshyyan, V.; Wen, Z.; Speck, N. A.; Battle, A.; Berger, S. L.; Wherry, E. J.; Shi, J.
Show abstract
Improving effector activity of antigen specific T cells is a major goal in cancer immunotherapy. Despite the identification of several effector T cell (TEFF)-driving transcription factors (TF), the transcriptional coordination of TEFF biology remains poorly understood. We developed an in vivo T cell CRISPR screening platform and identified a novel mechanism restraining TEFF biology through the ETS family TF, Fli1. Genetic deletion of Fli1 enhanced TEFF responses without compromising memory or exhaustion precursors. Fli1 restrained TEFF lineage differentiation by binding to cis-regulatory elements of effector-associated genes. Loss of Fli1 increased chromatin accessibility at ETS:RUNX motifs allowing more efficient Runx3-driven TEFF biology. CD8 T cells lacking Fli1 provided substantially better protection against multiple infections and tumors. These data indicate that Fli1 safeguards the developing CD8 T cell transcriptional landscape from excessive ETS:RUNX-driven TEFF cell differentiation. Moreover, genetic deletion of Fli1 improves TEFF differentiation and protective immunity in infections and cancer.
Matching journals
The top 5 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Cytotoxic CD4 Development Requires CD4 Effectors to Concurrently Recognize Local Antigen and Encounter Infection-Induced IL-15 97%
- Pre-existing chromatin accessibility and gene expression differences among naïve CD4+ T cells influence effector potential 97%
- ADAR1 interaction with Z-RNA promotes editing of endogenous double-stranded RNA and prevents MDA5-dependent immune activation. 96%
Similar papers in this journal
- A single-cell reference atlas delineates CD4+ T cell subtype-specific adaptation during acute and chronic viral infections 97%
- Delineating the transcriptional landscape and clonal diversity of virus- specific CD4 + T cells during chronic viral infection 96%
- The Atlas of the In Vivo HIV CD4 T Cell Reservoir 95%
Similar papers in this journal
Similar papers in this journal
- Human T-bet governs innate and innate-like adaptive IFN-γ immunity against mycobacteria 97%
- Serum Amyloid A Proteins Induce Pathogenic TH17 Cells and Promote Inflammatory Disease 96%
- Neoantigen-driven B cell and CD4+ T follicular helper cell collaboration promotes robust anti-tumor CD8+ T cell responses 96%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.