Atlas-guided discovery of transcription factors for T cell programming
Year: 2026
Type: article
Abstract: CD8+ T cells differentiate into diverse states that shape immune outcomes in cancer and chronic infection. To systematically define the transcription factors (TFs) driving these states, we built a comprehensive atlas integrating transcriptional and epigenetic data across nine CD8+ T cell states and inferred TF activity profiles. Our analysis catalogued TF activity fingerprints, uncovering regulatory mechanisms governing selective cell state differentiation. Leveraging this platform, we focused on two transcriptionally similar but functionally opposing states critical in tumor and viral contexts: terminally exhausted T cells (TEXterm), which are dysfunctional, and tissue-resident memory T cells (TRM), which are protective. Global TF community analysis revealed distinct biological pathways and TF-driven networks underlying protective versus dysfunctional states. Through in vivo CRISPR screening integrated with single-cell RNA sequencing (in vivo Perturb-seq), we delineated that TFs selectively govern TEXterm. We identified HIC1 and GFI1 as shared regulators of TEXterm and TRM differentiation and KLF6 as a unique regulator of TRM. Importantly, we discovered novel TEXterm single-state TFs, including ZSCAN20 and JDP2 with no prior known function in T cells. Targeted deletion of these TFs enhanced tumor control and synergized with immune checkpoint blockade. Consistently, their depletion in human T cells reduces the expression of inhibitory receptors and improves effector function. By decoupling exhaustion-selective from protective TRM programs, our platform enables more precise engineering of T cell states, advancing rational design of effective immunotherapies.
Source: Nature
Authors: H. Kay Chung, Cong Liu, Anamika Battu, Alexander N. Jambor, Brandon M. Pratt, Fucong Xie, Brian P. Riesenberg, Eduardo Casillas, Ming Sun, Elisa Landoni, Yanpei Li, Qidang Ye, Daniel Joo, Jarred Green, Zaid Syed, Nolan J. Brown, Matthew Smith, Shixin Ma, Shirong Tan, Brent Chick, Victoria Tripple, Z. Audrey Wang, Jun Wang, Bryan Mcdonald, Peixiang He, Qiyuan Yang, Timothy Chen, Siva Karthik Varanasi, Michael A. LaPorta, Thomas H. Mann, Dan Chen, Filipe Hoffmann, Josephine Ho, Jennifer Modliszewski, April Williams, Yusha Liu, Zhen Wang, Jieyuan Liu, Yiming Gao, Zhiting Hu, Ukrae H. Cho, Longwei Liu, Yingxiao Wang, Diana C. Hargreaves, Gianpietro Dotti, Barbara Savoldo, Jessica E. Thaxton, J. Justin Milner, Susan M. Kaech, Wei Wang
Institutions: University of North Carolina at Chapel Hill, Salk Institute for Biological Studies, UNC Lineberger Comprehensive Cancer Center, University of California San Diego, University of Southern California, University of California System, Texas A&M University, Allen Institute for Immunology, Allen Institute
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
OpenAlex ID: W7127563879