{"doi":"10.1073/pnas.2315419121","title":"Extraislet expression of islet antigen boosts T cell exhaustion to partially prevent autoimmune diabetes","abstract":"<jats:p>\n                    Persistent antigen exposure results in the differentiation of functionally impaired, also termed exhausted, T cells which are maintained by a distinct population of precursors of exhausted T (T\n                    <jats:sub>PEX</jats:sub>\n                    ) cells. T cell exhaustion is well studied in the context of chronic viral infections and cancer, but it is unclear whether and how antigen-driven T cell exhaustion controls progression of autoimmune diabetes and whether this process can be harnessed to prevent diabetes. Using nonobese diabetic (NOD) mice, we show that some CD8+ T cells specific for the islet antigen, islet-specific glucose-6-phosphatase catalytic subunit–related protein (IGRP) displayed terminal exhaustion characteristics within pancreatic islets but were maintained in the T\n                    <jats:sub>PEX</jats:sub>\n                    cell state in peripheral lymphoid organs (PLO). More IGRP-specific T cells resided in the PLO than in islets. To examine the impact of extraislet antigen exposure on T cell exhaustion in diabetes, we generated transgenic NOD mice with inducible IGRP expression in peripheral antigen-presenting cells. Antigen exposure in the extraislet environment induced severely exhausted IGRP-specific T cells with reduced ability to produce interferon (IFN)γ, which protected these mice from diabetes. Our data demonstrate that T cell exhaustion induced by delivery of antigen can be harnessed to prevent autoimmune diabetes.\n                  </jats:p>","journal":"Proceedings of the National Academy of Sciences","year":2024,"id":636245,"datarank":0.32958368660043297,"base_score":2.1972245773362196,"endowment":2.1972245773362196,"self_citation_contribution":0.32958368660043297,"citation_network_contribution":0.0,"self_endowment_contribution":0.32958368660043297,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1651167,"name":"Gaurang Jhala","orcid":"0009-0003-6187-5783","position":1,"is_corresponding":false},{"id":1651168,"name":"David J. De George","orcid":"0000-0002-7571-680X","position":2,"is_corresponding":false},{"id":1376579,"name":"Chun-Ting J. Kwong","orcid":null,"position":3,"is_corresponding":false},{"id":1651169,"name":"Marie K. Christensen","orcid":"0009-0001-8450-5780","position":4,"is_corresponding":false},{"id":1651170,"name":"Evan G. Pappas","orcid":null,"position":5,"is_corresponding":false},{"id":237857,"name":"Xin Liu","orcid":"0000-0003-0847-182X","position":6,"is_corresponding":false},{"id":1651171,"name":"Tingting Ge","orcid":null,"position":7,"is_corresponding":false},{"id":1651172,"name":"Prerak Trivedi","orcid":null,"position":8,"is_corresponding":false},{"id":656806,"name":"Axel Kallies","orcid":"0000-0002-6312-6968","position":9,"is_corresponding":false},{"id":581252,"name":"Helen E. Thomas","orcid":"0000-0001-6604-6640","position":10,"is_corresponding":false},{"id":921014,"name":"Thomas W. H. Kay","orcid":"0000-0002-7273-2556","position":11,"is_corresponding":false},{"id":1651173,"name":"Balasubramanian Krishnamurthy","orcid":"0000-0003-4735-2540","position":12,"is_corresponding":false},{"id":1651166,"name":"Claudia Selck","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Extraislet expression of islet antigen boosts T cell exhaustion to partially prevent autoimmune diabetes","abstract":"<jats:p>\n                    Persistent antigen exposure results in the differentiation of functionally impaired, also termed exhausted, T cells which are maintained by a distinct population of precursors of exhausted T (T\n                    <jats:sub>PEX</jats:sub>\n                    ) cells. T cell exhaustion is well studied in the context of chronic viral infections and cancer, but it is unclear whether and how antigen-driven T cell exhaustion controls progression of autoimmune diabetes and whether this process can be harnessed to prevent diabetes. Using nonobese diabetic (NOD) mice, we show that some CD8+ T cells specific for the islet antigen, islet-specific glucose-6-phosphatase catalytic subunit–related protein (IGRP) displayed terminal exhaustion characteristics within pancreatic islets but were maintained in the T\n                    <jats:sub>PEX</jats:sub>\n                    cell state in peripheral lymphoid organs (PLO). More IGRP-specific T cells resided in the PLO than in islets. To examine the impact of extraislet antigen exposure on T cell exhaustion in diabetes, we generated transgenic NOD mice with inducible IGRP expression in peripheral antigen-presenting cells. Antigen exposure in the extraislet environment induced severely exhausted IGRP-specific T cells with reduced ability to produce interferon (IFN)γ, which protected these mice from diabetes. Our data demonstrate that T cell exhaustion induced by delivery of antigen can be harnessed to prevent autoimmune diabetes.\n                  </jats:p>","is_dataset_classified":null,"base_score":2.1972245773362196,"endowment":2.1972245773362196,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"38285952","pmcid":"PMC10861925","openalex_id":"https://openalex.org/W4391304159","authors":[],"funders":[{"funder_name":"DHAC | NHMRC | National Institute for Dementia Research","grant_id":"GNT1150425","title":null},{"funder_name":"National Health and Medical Research Council (NHMRC)","grant_id":"1150425","title":"Intervening in the natural history of type 1 diabetes: an integrated approach"}],"total_grants":2,"fwci":2.7666,"citation_percentile":0.8959761,"influential_citations":0,"citation_trend":[{"year":2023,"count":1},{"year":2024,"count":3},{"year":2025,"count":1},{"year":2026,"count":3}],"oa_status":"hybrid","license":"cc-by-nc-nd","oa_locations":[{"url":"https://www.pnas.org/doi/pdf/10.1073/pnas.2315419121","host_type":"journal"},{"url":"https://www.pnas.org/doi/pdf/10.1073/pnas.2315419121","host_type":"publisher"},{"url":"https://pnas.org/doi/pdf/10.1073/pnas.2315419121","host_type":"publisher"},{"url":"http://dx.doi.org/10.1073/pnas.2315419121","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/38285952","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/10861925","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC10861925/pdf/pnas.202315419.pdf","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC10861925","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC10861925?pdf=render","host_type":"Europe_PMC"},{"url":"https://doi.org/10.1073/pnas.2315419121","host_type":""}],"fields_of_study":["Diabetes and associated disorders","Immune Cell Function and Interaction","Pancreatic function and diabetes","0301 basic medicine","0303 health sciences","03 medical and health sciences","Mice","Animals","Diabetes Mellitus, Type 1","Proteins","T-Cell Exhaustion","Glucose-6-Phosphatase","Mice, Transgenic","Mice, Inbred NOD","Islets of Langerhans","CD8-Positive T-Lymphocytes"],"mesh_terms":["T-Cell Exhaustion","Animals","Diabetes Mellitus, Type 1","Glucose-6-Phosphatase","Islets of Langerhans","Mice, Transgenic","Proteins","Mice, Inbred NOD","CD8-Positive T-Lymphocytes","Mice"],"keywords":["Immunology","NOD mice","Antigen","Biology","Nod","T cell","Islet","Autoimmunity","CD8","Population","Diabetes mellitus","Immune system","Endocrinology","Medicine","Tolerance","type 1 diabetes","T Cell Exhaustion","Proteins","Mice, Transgenic","Biological Sciences","CD8-Positive T-Lymphocytes","T-Cell Exhaustion","Mice","Islets of Langerhans","Diabetes Mellitus, Type 1","Mice, Inbred NOD","Glucose-6-Phosphatase","Animals"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-06T16:40:38.740411Z","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":[]}