{"doi":"10.3389/fendo.2021.622647","title":"Proinsulin-Reactive CD4 T Cells in the Islets of Type 1 Diabetes Organ Donors","abstract":"Proinsulin is an abundant protein that is selectively expressed by pancreatic beta cells and has been a focus for development of antigen-specific immunotherapies for type 1 diabetes (T1D). In this study, we sought to comprehensively evaluate reactivity to preproinsulin by CD4 T cells originally isolated from pancreatic islets of organ donors having T1D. We analyzed 187 T cell receptor (TCR) clonotypes expressed by CD4 T cells obtained from six T1D donors and determined their response to 99 truncated preproinsulin peptide pools, in the presence of autologous B cells. We identified 14 TCR clonotypes from four out of the six donors that responded to preproinsulin peptides. Epitopes were found across all of proinsulin (insulin B-chain, C-peptide, and A-chain) including four hot spot regions containing peptides commonly targeted by TCR clonotypes derived from multiple T1D donors. Of importance, these hot spots overlap with peptide regions to which CD4 T cell responses have previously been detected in the peripheral blood of T1D patients. The 14 TCR clonotypes recognized proinsulin peptides presented by various HLA class II molecules, but there was a trend for dominant restriction with HLA-DQ, especially T1D risk alleles DQ8, DQ2, and DQ8-trans. The characteristics of the tri-molecular complex including proinsulin peptide, HLA-DQ molecule, and TCR derived from CD4 T cells in islets, provides an essential basis for developing antigen-specific biomarkers as well as immunotherapies.","journal":"Frontiers in Endocrinology","year":2021,"id":167242,"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":32,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9571,"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":463866,"name":"A. Anderson","orcid":"0000-0001-9746-1257","position":1,"is_corresponding":false},{"id":262477,"name":"Holger A. Russ","orcid":"0000-0001-5117-2927","position":2,"is_corresponding":false},{"id":39947,"name":"Liping Yu","orcid":"0000-0003-0664-2154","position":3,"is_corresponding":false},{"id":694079,"name":"Sally C. Kent","orcid":"0000-0002-1543-8086","position":4,"is_corresponding":false},{"id":23929,"name":"Mark A. Atkinson","orcid":"0000-0001-8489-4782","position":5,"is_corresponding":false},{"id":389036,"name":"Clayton E. Mathews","orcid":"0000-0002-8817-6355","position":6,"is_corresponding":false},{"id":463868,"name":"Aaron W. Michels","orcid":"0000-0003-3766-5244","position":7,"is_corresponding":false},{"id":369808,"name":"Maki Nakayama","orcid":"0000-0002-0009-3687","position":8,"is_corresponding":false},{"id":463865,"name":"Laurie G. Landry","orcid":"0000-0002-4064-9109","position":0,"is_corresponding":true}],"reference_count":62,"raw_metadata":null,"created_at":"2026-07-18T23:45:54.042727Z","pmid":"33841327","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":[]}