Mapping self-associating chromatin hubs identifies Id proteins as key determinants of exhausted CD8+ T cell fate.

Wei Hu; Qing Chen; Shaoqi Zhu; Shengen Shawn Hu; Haibo Yu; Vanita Patel; Ying Wang; Vladimir P Badovinac; Yi Zhang; Chongzhi Zang; Weiqun Peng; Hai-Hui Xue

doi:10.1038/s41590-026-02578-4

PubMed · 42409948

Mapping self-associating chromatin hubs identifies Id proteins as key determinants of exhausted CD8+ T cell fate.

Wei Hu·Qing Chen·Shaoqi Zhu·Shengen Shawn Hu·Haibo Yu·Vanita Patel·Ying Wang·Vladimir P Badovinac·Yi Zhang·Chongzhi Zang·Weiqun Peng·Hai-Hui Xue

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Abstract

Within days of exposure to chronic viral infections, activated CD8+ T cells differentiate into Tcf1-Slamf6loTim3hi exhaustion-prone effector T (TEX_EFF) cells or self-renewing Tcf1+Slamf6hiTim3lo precursor exhausted T (TPEX) cells. Here we showed that early CD8+ TEX cell fates were imprinted by forming subset-specific, self-associating chromatin hubs. Chromatin hub assembly coincided with effector or stemness gene induction and identified the transcription cofactors Id2 and Id3 as key regulators that promoted CD8+ TEX_EFF and CD8+ TPEX cell fates, respectively. Id2 drove CD8+ TEX_EFF cell specification by activating effector genes, while suppressing genes involved in exhaustion and stemness. In contrast, Id3-repressed effector genes but upregulated IL-7Rα and AhR, thereby maintaining the CD8+ TPEX cell pool. Mechanistically, Id2 and Id3 exhibited a distinct impact on the chromatin accessibility landscape in early CD8+ TEX cells by engaging Runx3 and Tcf1 transcription factors along with E proteins. These findings indicated that reshaping chromatin architecture represents a critical means for specifying CD8+ TEX cell fates and ensuring lineage stability.

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Animals CD8-Positive T-Lymphocytes Inhibitor of Differentiation Proteins Inhibitor of Differentiation Protein 2 Chromatin T-Cell Exhaustion Mice Cell Differentiation Hepatocyte Nuclear Factor 1-alpha Core Binding Factor Alpha 3 Subunit Chromatin Assembly and Disassembly Lymphocyte Activation Mice, Inbred C57BL Mice, Knockout Journal Article

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Wei Hu, Qing Chen, Shaoqi Zhu, Shengen Shawn Hu, Haibo Yu, Vanita Patel, Ying Wang, Vladimir P Badovinac, Yi Zhang, Chongzhi Zang, Weiqun Peng, Hai-Hui Xue. 2026-07-06. Mapping self-associating chromatin hubs identifies Id proteins as key determinants of exhausted CD8+ T cell fate.. https://doi.org/10.1038/s41590-026-02578-4

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