DNA methylation profiling identifies TBKBP1 as potent amplifier of cytotoxic activity in CMV-specific human CD8+ T cells

Epigenetic mechanisms stabilize gene expression patterns during CD8+ T cell differentiation. Although adoptive transfer of virus-specific T cells is clinically applied to reduce the risk of virus infection or reactivation in immunocompromised individuals, the DNA methylation pattern of virus-specific CD8+ T cells is largely unknown. Hence, we here performed whole-genome bisulfite sequencing of cytomegalovirus-specific human CD8+ T cells and found that they display a unique DNA methylation pattern consisting of 79 differentially methylated regions (DMRs) when compared to memory CD8+ T cells. Among the top demethylated DMRs in cytomegalovirus-specific CD8+ T cells was TBKBP1, coding for TBK-binding protein 1 that can interact with TANK-binding kinase 1 (TBK1) and mediate pro-inflammatory responses in innate immune cells downstream of intracellular virus sensing. Since TBKBP1 has not yet been reported in T cells, we aimed to unravel its role in virus-specific CD8+ T cells. TBKBP1 demethylation in terminal effector CD8+ T cells correlated with higher TBKBP1 expression at both mRNA and protein level, independent of alternative splicing of TBKBP1 transcripts. Notably, the distinct DNA methylation patterns in CD8+ T cell subsets was stable upon long-term in vitro culture. TBKBP1 overexpression resulted in enhanced TBK1 phosphorylation upon stimulation of CD8+ T cells and significantly improved their virus neutralization capacity. Collectively, our data demonstrate that TBKBP1 modulates virus-specific CD8+ T cell responses and could be exploited as therapeutic target to improve adoptive T cell therapies.

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Journal
PLoS Pathogens
Published
2024-09-26
DOI
https://doi.org/10.1371/journal.ppat.1012581
Citations
3
Primary Topic
Immune Cell Function and Interaction
Type
article
Field-Weighted Citation Impact
0.72

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article

DNA methylation profiling identifies TBKBP1 as potent amplifier of cytotoxic activity in CMV-specific human CD8+ T cells

Melanie M. Brinkmann, Kilian Schober, Michael Beckstette, Jana Niemz et al.
3 citations
PLoS Pathogens
Immune Cell Function and Interaction
0.72
article

DNA methylation profiling identifies TBKBP1 as potent amplifier of cytotoxic activity in CMV-specific human CD8+ T cells

Melanie M. Brinkmann, Kilian Schober, Michael Beckstette, Jana Niemz, Andreas Keller, Philip Mausberg, Fawad Khan, Jochen Huehn, Stefan Floess, Britta Eiz‐Vesper, Christine S. Falk, Fabian Müller, Dirk Hans Busch, Agnes Bonifacius, Beate Pietzsch, Luka Čičin‐Šain, Philipp Hilgendorf, Varun Sasidharan-Nair, Thalea Buchta, Yu Zheng, Hosein Ahmadi
article en
3 citations

Abstract

Epigenetic mechanisms stabilize gene expression patterns during CD8+ T cell differentiation. Although adoptive transfer of virus-specific T cells is clinically applied to reduce the risk of virus infection or reactivation in immunocompromised individuals, the DNA methylation pattern of virus-specific CD8+ T cells is largely unknown. Hence, we here performed whole-genome bisulfite sequencing of cytomegalovirus-specific human CD8+ T cells and found that they display a unique DNA methylation pattern consisting of 79 differentially methylated regions (DMRs) when compared to memory CD8+ T cells. Among the top demethylated DMRs in cytomegalovirus-specific CD8+ T cells was TBKBP1, coding for TBK-binding protein 1 that can interact with TANK-binding kinase 1 (TBK1) and mediate pro-inflammatory responses in innate immune cells downstream of intracellular virus sensing. Since TBKBP1 has not yet been reported in T cells, we aimed to unravel its role in virus-specific CD8+ T cells. TBKBP1 demethylation in terminal effector CD8+ T cells correlated with higher TBKBP1 expression at both mRNA and protein level, independent of alternative splicing of TBKBP1 transcripts. Notably, the distinct DNA methylation patterns in CD8+ T cell subsets was stable upon long-term in vitro culture. TBKBP1 overexpression resulted in enhanced TBK1 phosphorylation upon stimulation of CD8+ T cells and significantly improved their virus neutralization capacity. Collectively, our data demonstrate that TBKBP1 modulates virus-specific CD8+ T cell responses and could be exploited as therapeutic target to improve adoptive T cell therapies.

PLoS PathogensVol. 20(9)
Friedrich-Alexander-Universität Erlangen-Nürnberg (DE), Medizinische Hochschule Hannover (DE), Universitätsklinikum Erlangen (DE), German Center for Infection Research (DE), Helmholtz Centre for Infection Research (DE), Helmholtz Institute for Pharmaceutical Research Saarland (DE), Centre for Individualised Infection Medicine (DE), Technical University of Munich (DE), Saarland University (DE), Technische Universität Braunschweig (DE)
Helmholtz-Gemeinschaft, Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Kowa Life Science Foundation, Medizinischen Hochschule Hannover, Federalno Ministarstvo Obrazovanja i Nauke
Good health and well-being
Openalex Percentile: Top 29%
Immune Cell Function and Interaction
0.72
DOIOpen Access PDFOpenAlex
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