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In this study, we report that maintenance of human memory CD8 T cell effector potential during in vitro and in vivo homeostatic proliferation is coupled to preservation of acquired DNA methylation programs. Whole-genome bisulfite sequencing of primary human naive, short-lived effector memory (TEM), and longer-lived central memory (TCM) and stem cell memory (TSCM) CD8 T cells identified effector molecules with demethylated promoters and poised for expression. Effector-loci demethylation was heritably preserved during IL-7\u2013 and IL-15\u2013mediated in vitro cell proliferation. Conversely, cytokine-driven proliferation of TCM and TSCM memory cells resulted in phenotypic conversion into TEM cells and was coupled to increased methylation of the CCR7 and Tcf7 loci. Furthermore, haploidentical donor memory CD8 T cells undergoing in vivo proliferation in lymphodepleted recipients also maintained their effector-associated demethylated status but acquired TEM-associated programs. These data demonstrate that effector-associated epigenetic programs are preserved during cytokine-driven subset interconversion of human memory CD8 T cells.<\/jats:p>","DOI":"10.1084\/jem.20161760","type":"journal-article","created":{"date-parts":[[2017,5,10]],"date-time":"2017-05-10T14:41:56Z","timestamp":1494427316000},"page":"1593-1606","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":143,"title":["Human memory CD8 T cell effector potential is epigenetically preserved during in vivo homeostasis"],"prefix":"10.1084","volume":"214","author":[{"given":"Hossam A.","family":"Abdelsamed","sequence":"first","affiliation":[{"name":"Department of Immunology, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ardiana","family":"Moustaki","sequence":"additional","affiliation":[{"name":"Department of Immunology, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiping","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Computational Biology, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pranay","family":"Dogra","sequence":"additional","affiliation":[{"name":"Department of Immunology, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hazem E.","family":"Ghoneim","sequence":"additional","affiliation":[{"name":"Department of Immunology, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caitlin C.","family":"Zebley","sequence":"additional","affiliation":[{"name":"Department of Immunology, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105 1"},{"name":"Department of Oncology, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8220-9980","authenticated-orcid":true,"given":"Brandon M.","family":"Triplett","sequence":"additional","affiliation":[{"name":"Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7816-4828","authenticated-orcid":true,"given":"Rafick-Pierre","family":"Sekaly","sequence":"additional","affiliation":[{"name":"Department of Pathology, Case Western Reserve University, Cleveland, OH 44106 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1261-9957","authenticated-orcid":true,"given":"Ben","family":"Youngblood","sequence":"additional","affiliation":[{"name":"Department of Immunology, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105 1"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2017,5,10]]},"reference":[{"key":"2023072604012258700_bib1","doi-asserted-by":"publisher","first-page":"912","DOI":"10.1016\/j.immuni.2009.05.006","article-title":"Genome-wide analysis of histone methylation reveals chromatin state-based regulation of gene transcription and function of memory CD8+ T cells","volume":"30","author":"Araki","year":"2009","journal-title":"Immunity."},{"key":"2023072604012258700_bib2","doi-asserted-by":"publisher","first-page":"4988","DOI":"10.4049\/jimmunol.1002042","article-title":"Cutting edge: The transcription factor eomesodermin enables CD8+ T cells to compete for the memory cell niche","volume":"185","author":"Banerjee","year":"2010","journal-title":"J. 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