{"doi":"10.1016/j.bpj.2021.08.027","title":"Height, but not binding epitope, affects the potency of synthetic TCR agonists","abstract":"Under physiological conditions, peptide-major histocompatibility complex (pMHC) molecules can trigger T cell receptors (TCRs) as monovalent ligands that are sparsely distributed on the plasma membrane of an antigen-presenting cell. TCRs can also be triggered by artificial clustering, such as with pMHC tetramers or antibodies; however, these strategies circumvent many of the natural ligand discrimination mechanisms of the T cell and can elicit nonphysiological signaling activity. We have recently introduced a synthetic TCR agonist composed of an anti-TCRβ Fab' antibody fragment covalently bound to a DNA oligonucleotide, which serves as a membrane anchor. This Fab'-DNA ligand efficiently triggers TCR as a monomer when membrane associated and exhibits a potency and activation profile resembling agonist pMHC. In this report, we explore the geometric requirements for efficient TCR triggering and cellular activation by Fab'-DNA ligands. We find that T cells are insensitive to the ligand binding epitope on the TCR complex but that length of the DNA tether is important. Increasing, the intermembrane distance spanned by Fab'-DNA:TCR complexes decreases TCR triggering efficiency and T cell activation potency, consistent with the kinetic-segregation model of TCR triggering. These results establish design parameters for constructing synthetic TCR agonists that are able to activate polyclonal T cell populations, such as T cells from a human patient, in a similar manner as the native pMHC ligand.","journal":"Biophysical Journal","year":2021,"id":179689,"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":18,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9534,"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":727399,"name":"Shumpei Morita","orcid":"0000-0003-0070-852X","position":1,"is_corresponding":false},{"id":344119,"name":"Darren B. McAffee","orcid":"0000-0002-2565-4938","position":2,"is_corresponding":false},{"id":727400,"name":"Sungi Kim","orcid":"0000-0002-0130-8643","position":3,"is_corresponding":false},{"id":727401,"name":"Mark K. O’Dair","orcid":"0000-0002-8113-2229","position":4,"is_corresponding":false},{"id":302378,"name":"Jay T. Groves","orcid":"0000-0002-3037-5220","position":5,"is_corresponding":false},{"id":510099,"name":"Kiera B. Wilhelm","orcid":"0000-0002-8781-7739","position":0,"is_corresponding":true}],"reference_count":75,"raw_metadata":null,"created_at":"2026-07-18T23:47:48.974996Z","pmid":"34453921","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":[]}