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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. Overall design: Peripheral blood mononuclear cells (PBMCs) from CMV-seropositive donors were were isolated, stimulated with CMV-pp65 overlapping peptide pool and subjected to flow cytometric sorting. Genomic DNA was isolated from sorted naive CD8+ T cells, interferon gamma-negative memory CD8+ T cells and interferon gamma-positive CD8+ T cells, and used for Bisulfite-Seq. Differentially methylated regions were identified by pairwise comparison of the samples with the software BSmooth."],"repository":["ENA"],"description_synonyms":["Thymus-Dependent Lymphocyte., 3110043L15Rik, cucumber mosaic virus CMV, Thymus-Dependent Lymphocytes, human being, Man (Taxonomy), Activity, T-Cells, ProSAPiP2, p32, Modern, Thymus-Dependent, Leu2, Prosapip2, T, Lymphocytes, cucumber mosaic virus, T-Lymphocyte, DNA methylation profiling, human, Cell, SINTBAD, Human, T Cells, Cytomegalovirus Infections, Homo sapiens, T Lymphocyte, T-Cell, CMV, Modern Man, Cells, T Cell, CMV Infections, cucumber mosaic cucumovirus CMV, CD8, MAL, T Lymphocytes, General activity, cucumber mosaic cucumovirus, Man, Thymus Dependent Lymphocytes, humans, Lymphocyte"],"name_synonyms":["Thymus-Dependent Lymphocyte., 3110043L15Rik, cucumber mosaic virus CMV, Thymus-Dependent Lymphocytes, human being, Man (Taxonomy), Activity, T-Cells, ProSAPiP2, p32, Modern, Thymus-Dependent, Leu2, Prosapip2, T, Lymphocytes, cucumber mosaic virus, T-Lymphocyte, DNA methylation profiling, human, Cell, SINTBAD, Human, T Cells, Cytomegalovirus Infections, Homo sapiens, T Lymphocyte, T-Cell, CMV, Modern Man, Cells, T Cell, CMV Infections, cucumber mosaic cucumovirus CMV, CD8, MAL, T Lymphocytes, General activity, cucumber mosaic cucumovirus, Man, Thymus Dependent Lymphocytes, humans, Lymphocyte"],"additional_accession":[]},"is_claimable":false,"name":"DNA methylation profiling identifies TBKBP1 as potent amplifier of cytotoxic activity in CMV-specific human CD8+ T cells","description":"DNA methylation profiling identifies TBKBP1 as potent amplifier of cytotoxic activity in CMV-specific human CD8+ T cells","dates":{"last_updated":"2025-09-24","first_public":"2024-09-15"},"accession":"PRJNA1030038","cross_references":{"GEO":["GSE245832"],"taxon":["9606"],"PubMed":["39325839"]}}