{"doi":"10.1101/2021.01.21.427654","title":"T cell circuits that sense antigen density with an ultrasensitive threshold","abstract":"Abstract Overexpressed tumor associated antigens (e.g. HER2 and EGFR) are attractive targets for therapeutic T cells, but toxic cross-reaction with normal tissues expressing low antigen levels has been observed with Chimeric Antigen Receptor (CAR) T cells targeting such antigens. Inspired by natural ultrasensitive response circuits, we engineer a two-step positive feedback circuit that allows T cells to discriminate targets based on a sigmoidal antigen density threshold. In this circuit, a low affinity SynNotch receptor for HER2 controls the expression of a high affinity CAR for HER2. Increasing HER2 density thus has cooperative effects on T cells ╌ it both increases CAR expression and activation ╌ leading to a sigmoidal response. T Cells with this circuit show sharp discrimination between target cells expressing normal and disease levels of HER2, both in vitro and in vivo . One Sentence Summary A two-step positive feedback circuit generates engineered T cells capable of killing target cells with an ultrasensitive antigen density threshold.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":213623,"datarank":0.4335557636844247,"base_score":2.8903717578961645,"endowment":2.8903717578961645,"self_citation_contribution":0.4335557636844247,"citation_network_contribution":0.0,"self_endowment_contribution":0.4335557636844247,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":17,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.954,"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":806202,"name":"Katie Cabral","orcid":null,"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":42,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:52:36.886828Z","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":[]}