Abstract
Background
Severe Omicron cases present profound lymphocytopenia, suggesting variant-specific immune injury.
Results
We identify CD63 as a conserved T-cell host factor supporting ACE2-independent SARS-CoV-2 entry. Despite lower intracellular viral loads than the ancestral strain, Omicron elicits enhanced T-cell apoptosis largely through a bystander mechanism. Omicron-stimulated epithelial cells secrete GDF15, which upregulates the pro-apoptotic protein BCL2L13 in T cells and thereby remotely accelerates apoptosis in uninfected bystanders. Functionally, recombinant GDF15 increases BCL2L13 and apoptosis, while genetic dampening of BCL2L13 blunts Omicron-specific high-intensity bystander death. In clinical samples, plasma GDF15 associates with mortality, SOFA scores, and lower lymphocyte counts, bridging the epithelial–immune axis to patient outcomes.
Conclusions
Our data delineate a two-track model of Omicron immune injury—CD63-enabled T-cell entry plus GDF15–BCL2L13-driven bystander apoptosis—that reconciles lower epithelial cytopathicity with deeper T-cell depletion in critical disease. These findings nominate the GDF15–BCL2L13 axis as a mechanistic marker and potential point of intervention.
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Data availability
The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium (https://proteomecentral.proteomexchange.org) via the iProX partner repository with the dataset identifiers PXD071450 and PXD071622. The RNA-seq data have been deposited in the OMIX database under accession numbers OMIX015179 and OMIX013909. The single-cell transcriptomics data have been deposited in the Gene Expression Omnibus (GEO) under accession number GSE312913. The anonymized dataset analyzed in this study can be made available upon reasonable request. Requests must be accompanied by a detailed research protocol and analysis plan, and must have appropriate institutional approvals, including data transfer agreements, in place prior to access. Requests should be formally addressed to Professor Haibo Qiu, Head of the Jiangsu Provincial Key Laboratory of Critical Care Medicine (haiboq2000@163.com).
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Acknowledgements
We extend our sincere gratitude to the Biosafety Level 3 Laboratory of Jiangsu Provincial Center for Disease Control and Prevention (China) for their support in viral infection experiments of this study. We also thank Shanghai OE Biotech Co., Ltd. for performing the RNA-Seq sequencing, and the Triple-TOF5600 & ZenoTOF 7600 Mass Spectrometry Platform at the Translational Medicine Center of Nanjing University Medical School for their technical assistance with proteomic sequencing.
Funding
Project supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project 2023ZD0506500, 2024ZD0530000, the Special Funds of the National Natural Science Foundation of China (82341032), the Natural Science Foundation of Jiangsu Province (BK20221413).
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All authors contributed to the study’s conception and design. Data collection and analysis were performed by CG; single-cell transcriptome data were analyzed by HC; SARS-CoV-2 experimental operations in the Biosafety Level 3 (BSL-3) laboratory were conducted by YC; molecular docking and data analysis were performed by JL and YT; XL, RY, NS, LL, and JX provided clinically relevant data support and revised the manuscript. JC, JX, HQ and SL supervised the study, were responsible for financial support, and oversaw corresponding authorship. The first draft of the manuscript was written by C.G., and all authors read and approved the final manuscript.
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Gao, C., Chen, H., Chi, Y. et al. Variant-divergent death: Omicron intensifies bystander T-cell apoptosis via GDF15–BCL2L13. Cell Death Discov. (2026). https://doi.org/10.1038/s41420-026-03079-x
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DOI: https://doi.org/10.1038/s41420-026-03079-x
