Journal article
Exhausted CD8 + T cell fate is programmed by dynamic CTCF-mediated enhancer activation and invariant CTCF-imposed barriers
Nature immunology
07/06/2026
DOI: 10.1038/s41590-026-02585-5
PMID: 42409949
Abstract
Exhausted CD8+ T (TEX) cells undergo extensive genome reorganization during differentiation, yet the drivers of this process remain elusive. Here we show that CTCF programmed CD8+ TEX cell fates through two distinct modes of action. CTCF acquired de novo binding sites and concordantly induced open chromatin in early CD8+ TEX cells responding to chronic viral infection. The dynamic CTCF binding activated enhancers and promoted chromatin looping. Consequently, genetic ablation of CTCF diminished chromatin accessibility and interaction strength, impairing CD8+ TEX cell proliferation, effector function and bioenergetic mobilization. Conversely, invariant CTCF binding acted as essential chromatin barriers, and loss of CTCF disrupted insulation and caused aberrant chromatin self-association and undue RNA polymerase II pausing, leading to excessive activation of exhaustion- and stemness-linked genes. Thus, CTCF balanced CD8+ TEX cell differentiation by gaining dynamic binding to induce cytotoxicity and sustain metabolic fitness, while its invariant binding compartmentalized exhaustion and stemness program genes to prevent their overexuberant activation.
Details
- Title: Subtitle
- Exhausted CD8 + T cell fate is programmed by dynamic CTCF-mediated enhancer activation and invariant CTCF-imposed barriers
- Creators
- Wei Hu - Hackensack University Medical CenterShaoqi Zhu - George Washington UniversityQing Chen - George Washington UniversityVladimir P Badovinac - University of IowaWeiqun Peng - George Washington UniversityHai-Hui Xue - New Jersey Veterans Affairs Health Care System, East Orange, NJ, USA. haihui.xue@hmh-cdi.org
- Resource Type
- Journal article
- Publication Details
- Nature immunology
- DOI
- 10.1038/s41590-026-02585-5
- PMID
- 42409949
- NLM abbreviation
- Nat Immunol
- ISSN
- 1529-2908
- eISSN
- 1529-2916
- Publisher
- Springer Nature
- Grant note
- CA290808 / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) AI191414 / U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID) AI112579 / U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID) AI139874 / U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID) AI187349 / U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID) BX005771 / U.S. Department of Veterans Affairs (Department of Veterans Affairs) AI121080 / U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID) AI114543 / U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID) 32500543 / National Natural Science Foundation of China (National Science Foundation of China)
- Language
- English
- Electronic publication date
- 07/06/2026
- Academic Unit
- Pathology
- Record Identifier
- 9985180967102771
Metrics
4 Record Views