{"doi":"10.3389/fcell.2020.619220","title":"MicroRNA-155 Controls iNKT Cell Development and Lineage Differentiation by Coordinating Multiple Regulating Pathways","abstract":"The development of invariant natural killer T ( i NKT) cells requires a well-attuned set of transcription factors, but how these factors are regulated and coordinated remains poorly understood. MicroRNA-155 (miR-155) is a key regulator of numerous cellular processes that affects cell development and homeostasis. Here, we found that miR-155 was highly expressed in early i NKT cells upon thymic selection, and then its expression is gradually downregulated during i NKT cell development. However, the mice with miR-155 germline deletion had normal i NKT cell development. To address if downregulated miR-155 is required for i NKT cell development, we made a CD4Cre.miR-155 knock-in (KI) mouse model with miR-155 conditional overexpression in the T cell lineage. Upregulated miR-155 led to interruption of i NKT cell development, diminished i NKT17 and i NKT1 cells, augmented i NKT2 cells, and these defects were cell intrinsic. Furthermore, defective i NKT cells in miR-155KI mice resulted in the secondary innate-like CD8 T cell development. Mechanistically, miR-155 modulated multiple targets and signaling pathways to fine tune i NKT cell development. MiR-155 modulated Jarid2 , a critical component of a histone modification complex, and Tab2 , the upstream activation kinase complex component of NF-κB, which function additively in i NKT development and in promoting balanced i NKT1/ i NKT2 differentiation. In addition, miR-155 also targeted Rictor , a signature component of mTORC2 that controls i NKT17 differentiation. Taken together, our results indicate that miR-155 serves as a key epigenetic regulator, coordinating multiple signaling pathways and transcriptional programs to precisely regulate i NKT cell development and functional lineage, as well as secondary innate CD8 T cell development.","journal":"Frontiers in Cell and Developmental Biology","year":2021,"id":195320,"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":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9545,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":766065,"name":"Kai Li","orcid":"0000-0002-3062-3618","position":1,"is_corresponding":false},{"id":766066,"name":"Xilin Zhang","orcid":"0000-0002-5204-4086","position":2,"is_corresponding":false},{"id":766067,"name":"Guihua Li","orcid":"0000-0002-5813-3872","position":3,"is_corresponding":false},{"id":766068,"name":"Tingting Liu","orcid":"0000-0003-2375-1299","position":4,"is_corresponding":false},{"id":582208,"name":"Xiaojun Wu","orcid":"0000-0002-7613-8415","position":5,"is_corresponding":false},{"id":766069,"name":"Stephen L. Brown","orcid":"0000-0001-9000-3501","position":6,"is_corresponding":false},{"id":334894,"name":"Li Zhou","orcid":"0000-0002-7028-3865","position":7,"is_corresponding":false},{"id":242437,"name":"Qing‐Sheng Mi","orcid":"0000-0002-1411-6827","position":8,"is_corresponding":false},{"id":486998,"name":"Jie Wang","orcid":"0000-0001-7870-0646","position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":null,"created_at":"2026-07-18T23:50:03.719152Z","pmid":"33585457","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":[]}