Epigenetic mechanisms play a critical role during differentiation of T cells by contributing to the formation of stable and heritable transcriptional patterns. To better understand the mechanisms of memory maintenance in CD8+ T cells, we performed genome-wide analysis of DNA methylation, histone marking (acetylated lysine 9 in histone H3 and trimethylated lysine 9 in histone), and gene-expression profiles in naive, effector memory (EM), and terminally differentiated EM (TEMRA) cells. Our results indicate that DNA demethylation and histone acetylation are coordinated to generate the transcriptional program associated with memory cells. Conversely, EM and TEMRA cells share a very similar epigenetic landscape. Nonetheless, the TEMRA transcriptional program predicts an innate immunity phenotype associated with genes never reported in these cells, including several mediators of NK cell activation (VAV3 and LYN) and a large array of NK receptors (e.g., KIR2DL3, KIR2DL4, KIR2DL1, KIR3DL1, KIR2DS5). In addition, we identified up to 161 genes that encode transcriptional regulators, some of unknown function in CD8+ T cells, and that were differentially expressed in the course of differentiation. Overall, these results provide new insights into the regulatory networks involved in memory CD8+ T cell maintenance and T cell terminal differentiation.
This work was supported by the Plan Nacional de I+D+I 2008–2011 and the European Union Fondos Feder, Instituto de Salud Carlos III (Grants PI12/02587 and PI16/01318), Red Española de Investigación Renal (Grants RD12/0021/0018, RD12/0021/0021, and RD16/0009/0020), and Plan de Ciencia, Tecnología e Innovación 2013–2017 del Principado de Asturias (GRUPIN-14-030). CIC bioGUNE support was provided by The Department of Industry, Tourism and Trade of the Government of the Autonomous Community of the Basque Country (Etortek Research Programs 2007–2015), the Innovation Technology Department of Bizkaia County, and the CIBER (Biomedical Research Networking Centre) program at Instituto de Salud Carlos III.
The sequences presented in this article have been submitted to the National Center for Biotechnology Information Gene Expression Omnibus under accession number GSE83159 (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE83159).
The online version of this article contains supplemental material.
Abbreviations used in this article:
- B lymphocyte–induced maturation protein 1
- CCAAT/enhancer binding protein δ
- chromatin immunoprecipitation
- differentially expressed gene
- differentially methylated region
- effector memory
- fold change
- false discovery rate
- gene ontology
- acetylated lysine 9 in histone H3
- trimethylated lysine 9 in histone H3
- Kyoto Encyclopedia of Genes and Genomes
- perforin 1
- terminally differentiated EM
- transcription start site
- zinc finger and SCAN domain containing protein 18.
- Received June 24, 2016.
- Accepted November 13, 2016.
- Copyright © 2017 by The American Association of Immunologists, Inc.