DNA methylation profiling identifies TBKBP1 as potent amplifier of cytotoxic activity in CMV-specific human CD8+ T cells. Yu, Z., Sasidharan-Nair, V., Buchta, T., Bonifacius, A., Khan, F., Pietzsch, B., Ahmadi, H., Beckstette, M., Niemz, J., Hilgendorf, P., Mausberg, P., Keller, A., Falk, C., Busch, D. H., Schober, K., Cicin-Sain, L., Müller, F., Brinkmann, M. M., Eiz-Vesper, B., Floess, S., & Huehn, J. PLOS Pathogens, 20(9):e1012581, 2024. doi abstract bibtex 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.
@article{Yu.2024,
year = {2024},
title = {{DNA methylation profiling identifies TBKBP1 as potent amplifier of cytotoxic activity in CMV-specific human CD8+ T cells}},
author = {Yu, Zheng and Sasidharan-Nair, Varun and Buchta, Thalea and Bonifacius, Agnes and Khan, Fawad and Pietzsch, Beate and Ahmadi, Hosein and Beckstette, Michael and Niemz, Jana and Hilgendorf, Philipp and Mausberg, Philip and Keller, Andreas and Falk, Christine and Busch, Dirk H. and Schober, Kilian and Cicin-Sain, Luka and Müller, Fabian and Brinkmann, Melanie M. and Eiz-Vesper, Britta and Floess, Stefan and Huehn, Jochen},
journal = {PLOS Pathogens},
issn = {1553-7366},
doi = {10.1371/journal.ppat.1012581},
pmid = {39325839},
pmcid = {PMC11460711},
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.}},
pages = {e1012581},
number = {9},
volume = {20}
}
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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.","pages":"e1012581","number":"9","volume":"20","bibtex":"@article{Yu.2024, \r\nyear = {2024}, \r\ntitle = {{DNA methylation profiling identifies TBKBP1 as potent amplifier of cytotoxic activity in CMV-specific human CD8+ T cells}}, \r\nauthor = {Yu, Zheng and Sasidharan-Nair, Varun and Buchta, Thalea and Bonifacius, Agnes and Khan, Fawad and Pietzsch, Beate and Ahmadi, Hosein and Beckstette, Michael and Niemz, Jana and Hilgendorf, Philipp and Mausberg, Philip and Keller, Andreas and Falk, Christine and Busch, Dirk H. and Schober, Kilian and Cicin-Sain, Luka and Müller, Fabian and Brinkmann, Melanie M. and Eiz-Vesper, Britta and Floess, Stefan and Huehn, Jochen}, \r\njournal = {PLOS Pathogens}, \r\nissn = {1553-7366}, \r\ndoi = {10.1371/journal.ppat.1012581}, \r\npmid = {39325839}, \r\npmcid = {PMC11460711}, \r\nabstract = {{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.}}, \r\npages = {e1012581}, \r\nnumber = {9}, \r\nvolume = {20}\r\n}\r\n","author_short":["Yu, Z.","Sasidharan-Nair, V.","Buchta, T.","Bonifacius, A.","Khan, F.","Pietzsch, B.","Ahmadi, H.","Beckstette, M.","Niemz, J.","Hilgendorf, P.","Mausberg, P.","Keller, A.","Falk, C.","Busch, D. H.","Schober, K.","Cicin-Sain, L.","Müller, F.","Brinkmann, M. 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