{"doi":"10.1101/2020.11.02.365148","title":"IL-12 signaling promotes TET2-mediated DNA demethylation during CD8 T cell effector differentiation","abstract":"SUMMARY CD8 T cell memory differentiation endows T cells with an ability to rapidly induce effector functions upon pathogen re-encounter. While it is well established that substantial epigenetic remodeling occurs during the effector stage of the immune response, the signaling events that imprint CD8 T cells with these stable epigenetic programs are not well-defined. To gain insight into the signaling determinants of effector-associated epigenetic programming among CD8 T cells, we explored the role of IL-12 in the imprinting of IFNg expression during human CD8 T cell priming. We observed that TCR-mediated stimulation of human naïve CD8 T cells is not sufficient to induce substantial demethylation of the IFNg promotor. However, TCR stimulation in the presence of the inflammatory cytokine, IL-12, resulted in significant and stable demethylation of the IFNg locus that was commensurate with an increase in IFNg expression. We further show that IL-12-associated demethylation of the IFNg locus is coupled to cell division through TET2-dependent passive demethylation in an ex vivo human CAR T cell model system and an in vivo immunologically competent murine system. Collectively, these data illustrate that IL-12 signaling promotes TET2-mediated effector epigenetic programming in CD8 T cells during the primary immune response and serve as proof of concept that signal 3 cytokines can be used to guide the induction of epigenetically regulated traits among T cells used for adoptive immunotherapies.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":131471,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9474,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":271004,"name":"Hossam A. Abdelsamed","orcid":"0000-0002-5448-6056","position":1,"is_corresponding":false},{"id":271008,"name":"Hazem E. Ghoneim","orcid":"0000-0002-9816-4286","position":2,"is_corresponding":false},{"id":271009,"name":"Shanta Alli","orcid":"0000-0003-1692-1616","position":3,"is_corresponding":false},{"id":260229,"name":"Dalia Haydar","orcid":"0000-0002-7959-2699","position":4,"is_corresponding":false},{"id":586264,"name":"Tarsha Harris","orcid":null,"position":5,"is_corresponding":false},{"id":271011,"name":"Maureen A. McGargill","orcid":"0000-0002-0916-0372","position":6,"is_corresponding":false},{"id":260238,"name":"Giedre Krenciute","orcid":"0000-0003-4335-0644","position":7,"is_corresponding":false},{"id":250684,"name":"Ben Youngblood","orcid":"0000-0002-1261-9957","position":8,"is_corresponding":false},{"id":271005,"name":"Caitlin C. Zebley","orcid":"0000-0002-8419-4660","position":0,"is_corresponding":true}],"reference_count":43,"raw_metadata":null,"created_at":"2026-07-18T23:16:03.875886Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}