{"doi":"10.3389/fimmu.2024.1415102","title":"CD39 delineates chimeric antigen receptor regulatory T cell subsets with distinct cytotoxic & regulatory functions against human islets","abstract":"Human regulatory T cells (Treg) suppress other immune cells. Their dysfunction contributes to the pathophysiology of autoimmune diseases, including type 1 diabetes (T1D). Infusion of Tregs is being clinically evaluated as a novel way to prevent or treat T1D. Genetic modification of Tregs, most notably through the introduction of a chimeric antigen receptor (CAR) targeting Tregs to pancreatic islets, may improve their efficacy. We evaluated CAR targeting of human Tregs to monocytes, a human β cell line and human islet β cells in vitro . Targeting of HLA-A2-CAR (A2-CAR) bulk Tregs to HLA-A2 + cells resulted in dichotomous cytotoxic killing of human monocytes and islet β cells. In exploring subsets and mechanisms that may explain this pattern, we found that CD39 expression segregated CAR Treg cytotoxicity. CAR Tregs from individuals with more CD39 low/- Tregs and from individuals with genetic polymorphism associated with lower CD39 expression (rs10748643) had more cytotoxicity. Isolated CD39 − CAR Tregs had elevated granzyme B expression and cytotoxicity compared to the CD39 + CAR Treg subset. Genetic overexpression of CD39 in CD39 low CAR Tregs reduced their cytotoxicity. Importantly, β cells upregulated protein surface expression of PD-L1 and PD-L2 in response to A2-CAR Tregs. Blockade of PD-L1/PD-L2 increased β cell death in A2-CAR Treg co-cultures suggesting that the PD-1/PD-L1 pathway is important in protecting islet β cells in the setting of CAR immunotherapy. In summary, introduction of CAR can enhance biological differences in subsets of Tregs. CD39 + Tregs represent a safer choice for CAR Treg therapies targeting tissues for tolerance induction.","journal":"Frontiers in Immunology","year":2024,"id":434159,"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":13,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9551,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1031693,"name":"Pin-I Chen","orcid":null,"position":1,"is_corresponding":false},{"id":467422,"name":"Robert L. Whitener","orcid":"0000-0002-0931-3586","position":2,"is_corresponding":false},{"id":422166,"name":"Matthew S. MacDougall","orcid":"0000-0002-7946-6721","position":3,"is_corresponding":false},{"id":1092084,"name":"Vy M. N. Coykendall","orcid":null,"position":4,"is_corresponding":false},{"id":1240313,"name":"Hao Yan","orcid":"0000-0003-0796-8076","position":5,"is_corresponding":false},{"id":1210031,"name":"Yong Bin Kim","orcid":"0009-0002-8959-2630","position":6,"is_corresponding":false},{"id":1240314,"name":"William Harper","orcid":"0000-0002-0486-2180","position":7,"is_corresponding":false},{"id":1240835,"name":"Shiva Pathak","orcid":null,"position":8,"is_corresponding":false},{"id":946590,"name":"Bettina P. Iliopoulou","orcid":null,"position":9,"is_corresponding":false},{"id":1240836,"name":"Allison Hestor","orcid":null,"position":10,"is_corresponding":false},{"id":250523,"name":"Diane C. Saunders","orcid":"0000-0002-8849-6746","position":11,"is_corresponding":false},{"id":343972,"name":"Erick Spears","orcid":"0000-0003-3345-1724","position":12,"is_corresponding":false},{"id":740924,"name":"Jean Sévigny","orcid":"0000-0003-2922-1600","position":13,"is_corresponding":false},{"id":42063,"name":"David M. Maahs","orcid":"0000-0002-4602-7909","position":14,"is_corresponding":false},{"id":411586,"name":"Marina Basina","orcid":"0009-0004-3192-6989","position":15,"is_corresponding":false},{"id":497602,"name":"Seth A. Sharp","orcid":"0000-0002-0607-9990","position":16,"is_corresponding":false},{"id":7383,"name":"Anna L. Gloyn","orcid":"0000-0003-1205-1844","position":17,"is_corresponding":false},{"id":7379,"name":"Alvin C. Powers","orcid":"0000-0003-1941-5786","position":18,"is_corresponding":false},{"id":44518,"name":"Seung K. Kim","orcid":"0000-0001-6135-7810","position":19,"is_corresponding":false},{"id":411584,"name":"Kent P. Jensen","orcid":"0000-0001-9721-4379","position":20,"is_corresponding":false},{"id":381361,"name":"Everett Meyer","orcid":"0000-0001-7953-853X","position":21,"is_corresponding":false},{"id":1240312,"name":"Xiangni Wu","orcid":"0000-0002-9363-7064","position":0,"is_corresponding":true}],"reference_count":41,"raw_metadata":null,"created_at":"2026-07-19T01:59:53.957667Z","pmid":"39007132","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":[]}