Epigenetically Controlled ZEB2 Expression Promotes the Cytotoxic Potential of CMV-Specific CD8⁺ T Cells.

Varun Sasidharan Nair, Zheng Yu, Hosein Ahmadi, Agnes Bonifacius, Beate Pietzsch, Dirk H Busch, Luka Cicin-Sain, Fabian Müller, Kilian Schober, Britta Eiz-Vesper, Stefan Floess, Jochen Huehn

Journal: European journal of immunology 2025;55(11):e70084

PMID: 41195865

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Abstract

Zinc finger E-box binding protein 2 (ZEB2) is a key factor in the differentiation of naïve CD8⁺ T cells into effector and memory T cells. However, the precise regulatory role of ZEB2 in cytotoxic CD8⁺ T cells remains unknown. Our recent DNA methylation analysis of cytomegalovirus (CMV)-specific human CD8⁺ T cells revealed two differentially methylated regions (DMRs) within the ZEB2 locus. In the present study, we show that these ZEB2 DMRs undergo pronounced demethylation during T cell differentiation. In particular, terminally differentiated CD8⁺ T cells and cytotoxic CD4⁺ T cells show an almost complete demethylation. Demethylation of the ZEB2 DMRs correlates strongly with ZEB2 expression in all T cell subsets. Furthermore, DNA methylation patterns remain stable during long-term in vitro culture. ZEB2 knockout in CD8⁺ effector T cells results in altered gene expression profiles, affecting genes related to cell-cell adhesion and impairing the cytotoxic capacity in CMV-specific killing assays. Our data show that ZEB2 expression contributes to the differentiation of naïve CD8⁺ T cells into effector and memory T cells and regulates the functional properties of virus-specific cytotoxic CD8⁺ T cells.

Address: Department Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.; Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany.; German Center for Infection Research (DZIF), Thematic Translation Unit-Immunocompromised Host (TTU-IICH), Partner Site Hannover-, Braunschweig, Germany.; nextGENERATION Medical Scientist Program, Dean's Office For Academic Career Development, Hannover Medical School, Hannover, Germany.; Institute For Medical Microbiology, Immunology and Hygiene, Technical University Munich (TUM), Munich, Germany.; German Center for Infection Research (DZIF), Thematic Translation Unit-Immunocompromised Host (TTU-IICH), Partner Site, Munich, Germany.; German Center for Infection Research (DZIF), Thematic Translation Unit-Immunocompromised Host (TTU-IICH), Partner Site Hannover-, Braunschweig, Germany.; Department of Viral Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.; Center For Individualised Infection Medicine (CiiM), a Joint Venture Between the Hannover Medical School and the Helmholtz Centre For Infection Research, Hannover, Germany.; Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany.; Integrative Cellular Biology and Bioinformatics, Saarland University, Saarbrücken, Germany.; Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie Und Hygiene, Universitätsklinikum Erlangen Und Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany.; FAU Profile Center Immunomedicine, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany.; Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany.; German Center for Infection Research (DZIF), Thematic Translation Unit-Immunocompromised Host (TTU-IICH), Partner Site Hannover-, Braunschweig, Germany.; Department Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.; Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany.

DOI: 10.1002/eji.70084

MeSH Terms: Zinc Finger E-box Binding Homeobox 2, Humans, Cytomegalovirus, Epigenesis, Genetic, CD8-Positive T-Lymphocytes, DNA Methylation, Cell Differentiation, Cytomegalovirus Infections, Cytotoxicity, Immunologic, Immunologic Memory, T-Lymphocytes, Cytotoxic, Cells, Cultured, Gene Expression Regulation

Epigenetically Controlled ZEB2 Expression Promotes the Cytotoxic Potential of CMV-Specific CD8+ T Cells.

Abstract

Epigenetically Controlled ZEB2 Expression Promotes the Cytotoxic Potential of CMV-Specific CD8⁺ T Cells.