Histone methyltransferase NSD2 shapes CD8 ⁺ T cell fates through the H3K36me2- Zbtb20 axis
10 affiliations
- 1Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
- 2Department of Laboratory Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
- 3Department of Otolaryngology–Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
- 4Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
- 5Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
- 6State Key Laboratory of Oncology in South China, Department of Experiment Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, Guangdong, China.
- 7Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm 17165, Sweden.
- 8The Second Affiliated Hospital of Guangzhou Medical University, Guangdong Provincial Key Laboratory of Allergy and Clinical Immunology, Guangzhou 510260, China.
- 9Department of Physiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
- 10State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Disease, Huazhong University of Science and Technology, Wuhan 430030, China.
Abstract
CD8⁺ T cells, as the most important cytolytic cells in adaptive immunity, can differentiate into distinct subpopulations with specific functions and fates. During this process, CD8⁺ T cells exhibit substantial plasticity in their differentiation trajectory. Notably, epigenetic regulation has emerged as a pivotal mechanism to govern T cell fate decisions. In this study, we demonstrate that the histone methyltransferase NSD2 critically regulates CD8⁺ T cell differentiation during acute viral infection. While NSD2 deficiency enhances the early expansion of activated CD8⁺ T cells, it severely compromises their survival fitness during the contraction phase, leading to a disproportionate collapse of the antigen-specific pool and limiting the establishment of robust long-lived memory. Mechanistically, this defect is driven by the disruption of the H3K36me2-Zbtb20 regulatory axis. Furthermore, we show that in the absence of NSD2, CD8⁺ T cells in tumor exhibit an increased proportion but dysfunctional resident memory T cell phenotype. Collectively, our findings highlight a critical role for NSD2 in providing more mechanistic insights into how epigenetic mechanisms fine-tune T cell differentiation.
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BibTeX
@article{yuan2026histone,
title = {{Histone methyltransferase NSD2 shapes CD8 ⁺ T cell fates through the H3K36me2- Zbtb20 axis}},
author = {Shijie Yuan and Yifan Xu and Huicheng Liu and Ying Xue and Mengdi Zhu and Xiaorong Xie and Xuwei Wu and Yuting Xia and Lin Li and Yuan Luo and Zehan Huang and Xiangping Yang and Huiyun Du and Ran He},
journal = {Science Advances},
year = {2026},
month = oct,
doi = {10.1126/sciadv.aee9670},
url = {https://www.science.org/doi/10.1126/sciadv.aee9670},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Histone methyltransferase NSD2 shapes CD8 ⁺ T cell fates through the H3K36me2- Zbtb20 axis
AU - Shijie Yuan
AU - Yifan Xu
AU - Huicheng Liu
AU - Ying Xue
AU - Mengdi Zhu
AU - Xiaorong Xie
AU - Xuwei Wu
AU - Yuting Xia
AU - Lin Li
AU - Yuan Luo
AU - Zehan Huang
AU - Xiangping Yang
AU - Huiyun Du
AU - Ran He
PY - 2026
DA - 2026/10/23
JO - Science Advances
DO - 10.1126/sciadv.aee9670
UR - https://www.science.org/doi/10.1126/sciadv.aee9670
AB - CD8⁺ T cells, as the most important cytolytic cells in adaptive immunity, can differentiate into distinct subpopulations with specific functions and fates. During this process, CD8⁺ T cells exhibit substantial plasticity in their differentiation trajectory. Notably, epigenetic regulation has emerged as a pivotal mechanism to govern T cell fate decisions. In this study, we demonstrate that the histone methyltransferase NSD2 critically regulates CD8⁺ T cell differentiation during acute viral infection. While NSD2 deficiency enhances the early expansion of activated CD8⁺ T cells, it severely compromises their survival fitness during the contraction phase, leading to a disproportionate collapse of the antigen-specific pool and limiting the establishment of robust long-lived memory. Mechanistically, this defect is driven by the disruption of the H3K36me2-Zbtb20 regulatory axis. Furthermore, we show that in the absence of NSD2, CD8⁺ T cells in tumor exhibit an increased proportion but dysfunctional resident memory T cell phenotype. Collectively, our findings highlight a critical role for NSD2 in providing more mechanistic insights into how epigenetic mechanisms fine-tune T cell differentiation.
SN - 2375-2548
ER -