T/NK-cell remodeling and IFN-responsive myeloid activation delineate immunometabolic risk profiles in chronic active Epstein-Barr virus disease
- 1Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University
- 2Shanghai Sci-Tech Inno Center for Infection & Immunity
- 3Key Laboratory of Medical Molecular Virology (MOE/MOH), Shanghai Medical College, Fudan University
Abstract
Background: Chronic active Epstein-Barr virus disease (CAEBV) is a rare EBV-associated T/NK-cell lymphoproliferative disorder characterized by persistent viral infection, systemic inflammation, and highly variable clinical courses. Patients may develop HLH-like hyperinflammation, severe organ involvement, lymphoma transformation, or death, yet current assessment does not fully explain why patients with similar viral burden follow divergent trajectories.
Methods: We integrated PBMC single-cell RNA-sequencing profiles from healthy controls and CAEBV samples with a retrospective cohort of 130 independent CAEBV patients to connect cellular immune remodeling with clinically measurable features.
Results: Single-cell analysis identified T/NK remodeling toward cytotoxic, exhaustion-associated, senescence-associated, and metabolically altered states, accompanied by IFN-responsive, antigen-presenting myeloid programs. Ligand-receptor and receiver-side analyses prioritized candidate IFNγ-associated T/NK-to-myeloid communication within this IFN-responsive program, linking NK and CD8+ T-cell states with myeloid inflammatory activation. Guided by these findings, we mapped inflammatory, metabolic, coagulation, and lymphocyte-subset variables into a biology-informed clinical immunometabolic index reflecting inflammatory cytokine activation, metabolic stress, and adaptive immune contraction. Internally defined index strata were associated with increasing CAEBV+HLH, death, and severe-disease burden. Unsupervised clinical mapping further identified three exploratory but interpretable immunometabolic patterns, including immune-metabolically preserved, intermediate immune-contraction, and IFNγ-high immunometabolic high-risk, with distinct immune-cell, inflammatory, metabolic, and outcome profiles.
Conclusions: Together, these findings organize CAEBV heterogeneity around linked T/NK remodeling, myeloid activation, and systemic immunometabolic stress. This single-cell-informed clinical-pattern map complements EBV-DNA and organ-size assessment and supports prospective validation of clinically measurable, mechanism-guided monitoring and intervention strategies.
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BibTeX
@article{cao2026tnkcell,
title = {{T/NK-cell remodeling and IFN-responsive myeloid activation delineate immunometabolic risk profiles in chronic active Epstein-Barr virus disease}},
author = {Yue Cao and Zhe Zhou and Shenglei Yu and Yanying Liang and Chenxi Zhao and Xvrong Li and Zenghui Zhang and Jianming Zheng and Qiaoling Ruan and Yan Gao and Qingluan Yang and Lingyun Shao and Wenhong Zhang},
journal = {Frontiers in Immunology},
year = {2026},
month = nov,
doi = {10.3389/fimmu.2026.1928095},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1928095/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - T/NK-cell remodeling and IFN-responsive myeloid activation delineate immunometabolic risk profiles in chronic active Epstein-Barr virus disease
AU - Yue Cao
AU - Zhe Zhou
AU - Shenglei Yu
AU - Yanying Liang
AU - Chenxi Zhao
AU - Xvrong Li
AU - Zenghui Zhang
AU - Jianming Zheng
AU - Qiaoling Ruan
AU - Yan Gao
AU - Qingluan Yang
AU - Lingyun Shao
AU - Wenhong Zhang
PY - 2026
DA - 2026/11/03
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1928095
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1928095/full
AB - Background: Chronic active Epstein-Barr virus disease (CAEBV) is a rare EBV-associated T/NK-cell lymphoproliferative disorder characterized by persistent viral infection, systemic inflammation, and highly variable clinical courses. Patients may develop HLH-like hyperinflammation, severe organ involvement, lymphoma transformation, or death, yet current assessment does not fully explain why patients with similar viral burden follow divergent trajectories. Methods: We integrated PBMC single-cell RNA-sequencing profiles from healthy controls and CAEBV samples with a retrospective cohort of 130 independent CAEBV patients to connect cellular immune remodeling with clinically measurable features. Results: Single-cell analysis identified T/NK remodeling toward cytotoxic, exhaustion-associated, senescence-associated, and metabolically altered states, accompanied by IFN-responsive, antigen-presenting myeloid programs. Ligand-receptor and receiver-side analyses prioritized candidate IFNγ-associated T/NK-to-myeloid communication within this IFN-responsive program, linking NK and CD8+ T-cell states with myeloid inflammatory activation. Guided by these findings, we mapped inflammatory, metabolic, coagulation, and lymphocyte-subset variables into a biology-informed clinical immunometabolic index reflecting inflammatory cytokine activation, metabolic stress, and adaptive immune contraction. Internally defined index strata were associated with increasing CAEBV+HLH, death, and severe-disease burden. Unsupervised clinical mapping further identified three exploratory but interpretable immunometabolic patterns, including immune-metabolically preserved, intermediate immune-contraction, and IFNγ-high immunometabolic high-risk, with distinct immune-cell, inflammatory, metabolic, and outcome profiles. Conclusions: Together, these findings organize CAEBV heterogeneity around linked T/NK remodeling, myeloid activation, and systemic immunometabolic stress. This single-cell-informed clinical-pattern map complements EBV-DNA and organ-size assessment and supports prospective validation of clinically measurable, mechanism-guided monitoring and intervention strategies.
SN - 1664-3224
ER -