{"doi":"10.1126/science.abc1855","title":"T cell circuits that sense antigen density with an ultrasensitive threshold","abstract":"Overexpressed tumor-associated antigens [for example, epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2)] are attractive targets for therapeutic T cells, but toxic \"off-tumor\" cross-reaction with normal tissues that express low levels of target antigen can occur with chimeric antigen receptor (CAR)-T cells. Inspired by natural ultrasensitive response circuits, we engineered a two-step positive-feedback circuit that allows human cytotoxic T cells to discriminate targets on the basis of a sigmoidal antigen-density threshold. In this circuit, a low-affinity synthetic Notch receptor for HER2 controls the expression of a high-affinity CAR for HER2. Increasing HER2 density thus has cooperative effects on T cells-it increases both CAR expression and activation-leading to a sigmoidal response. T cells with this circuit show sharp discrimination between target cells expressing normal amounts of HER2 and cancer cells expressing 100 times as much HER2, both in vitro and in vivo.","journal":"Science","year":2021,"id":146930,"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":186,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9555,"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":256490,"name":"Wei Yu","orcid":"0000-0002-3154-5084","position":1,"is_corresponding":false},{"id":625095,"name":"Katelyn A. Cabral","orcid":"0000-0002-5161-1018","position":2,"is_corresponding":false},{"id":625096,"name":"Olivia A. Creasey","orcid":"0000-0002-9225-6278","position":3,"is_corresponding":false},{"id":256018,"name":"Maria del Pilar Lopez Pazmino","orcid":"0000-0003-3219-6944","position":4,"is_corresponding":false},{"id":625097,"name":"Yurie Tonai","orcid":"0000-0001-9610-6667","position":5,"is_corresponding":false},{"id":626625,"name":"Arsenia De Guzman","orcid":null,"position":6,"is_corresponding":false},{"id":625098,"name":"Anna R. Mäkelä","orcid":"0009-0002-9314-6828","position":7,"is_corresponding":false},{"id":568538,"name":"Kalle Saksela","orcid":"0000-0003-0827-122X","position":8,"is_corresponding":false},{"id":5492,"name":"Zev J. Gartner","orcid":"0000-0001-7803-1219","position":9,"is_corresponding":false},{"id":256019,"name":"Wendell A. Lim","orcid":"0000-0003-4052-8056","position":10,"is_corresponding":false},{"id":273968,"name":"Rogelio A. Hernández‐López","orcid":"0000-0003-3968-4908","position":0,"is_corresponding":true}],"reference_count":33,"raw_metadata":null,"created_at":"2026-07-18T23:42:30.206628Z","pmid":"33632893","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":[]}