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 DH, Schober K, Cicin-Sain L, Müller F, Brinkmann MM, Eiz-Vesper B, Floess S, Huehn J (2024)

Publication Type: Journal article

Publication year: 2024

Journal

PLoS Pathogens Public Library of Science

Book Volume: 20

Article Number: e1012581

Journal Issue: 9 September

DOI: 10.1371/journal.ppat.1012581

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.

Authors with CRIS profile

Philipp Hilgendorf Institute of Microbiology – Clinical Microbiology, Immunology and Hygiene Kilian Schober Institute of Microbiology – Clinical Microbiology, Immunology and Hygiene

Involved external institutions

Helmholtz-Zentrum für Infektionsforschung (HZI) DE Germany (DE) Technische Universität Braunschweig DE Germany (DE) Medizinische Hochschule Hannover (MHH) / Hannover Medical School DE Germany (DE) Universität des Saarlandes (UdS) DE Germany (DE) Technische Universität München (TUM) DE Germany (DE)

How to cite

APA:

Yu, Z., Sasidharan-Nair, V., Buchta, T., Bonifacius, A., Khan, F., Pietzsch, B.,... Huehn, J. (2024). DNA methylation profiling identifies TBKBP1 as potent amplifier of cytotoxic activity in CMV-specific human CD8+ T cells. PLoS Pathogens, 20(9 September). https://doi.org/10.1371/journal.ppat.1012581

MLA:

Yu, Zheng, et al. "DNA methylation profiling identifies TBKBP1 as potent amplifier of cytotoxic activity in CMV-specific human CD8+ T cells." PLoS Pathogens 20.9 September (2024).

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