{"doi":"10.3389/fimmu.2025.1504583","title":"Dysfunctional β-cell autophagy induces β-cell stress and enhances islet immunogenicity","abstract":"Background Type 1 Diabetes (T1D) is caused by a combination of genetic and environmental factors that trigger autoimmune-mediated destruction of pancreatic β-cells. Defects in β-cell stress response pathways such as autophagy may play an important role in activating and/or exacerbating the immune response in disease development. Previously, we discovered that β-cell autophagy is impaired prior to the onset of T1D, implicating this pathway in T1D pathogenesis. Aims To assess the role of autophagy in β-cell health and survival, and whether defects in autophagy render islets more immunogenic. Methods We knocked out the critical autophagy enzyme, ATG7, in the β-cells of mice (ATG7 Δβ-cell ) then monitored blood glucose, performed glucose tolerance tests, and evaluated bulk islet mRNA and protein. We also assessed MHC-I expression and presence of CD45+ immune cells in ATG7 Δβ-cell islets and evaluated how impaired autophagy affects EndoC-βH1 HLA-I expression under basal and IFNα stimulated conditions. Lastly, we co-cultured ATG7 Δβ-cell islet cells with diabetogenic BDC2.5 helper T cells and evaluated T cell activation. Results We found that all ATG7 Δβ-cell mice developed diabetes between 11-15 weeks of age. Gene ontology analysis revealed a significant upregulation of pathways involved in inflammatory processes, response to ER stress, and the ER-associated degradation pathway. Interestingly, we also observed upregulation of proteins involved in MHC-I presentation, suggesting that defective β-cell autophagy may alter the immunopeptidome, or antigen repertoire, and enhance β-cell immune visibility. In support of this hypothesis, we observed increased MHC-I expression and CD45+ immune cells in ATG7 Δβ-cell islets. We also demonstrate that HLA-I is upregulated in EndoC β-cells when autophagic degradation is inhibited. This effect was observed under both basal and IFNα stimulated conditions. Conversely, a stimulator of lysosome acidification/function, C381, decreased HLA-I expression. Lastly, we showed that in the presence of islet cells with defective autophagy, there is enhanced BDC2.5 T cell activation. Conclusions Our findings demonstrate that β-cell autophagy is critical to cell survival/function. Defective β-cell autophagy induces ER stress, alters pathways of antigen production, and enhances MHC-I/HLA-I presentation to surveilling immune cells. Overall, our results suggest that defects in autophagy make β-cells more susceptible to immune attack and destruction.","journal":"Frontiers in Immunology","year":2025,"id":511697,"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":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9572,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":563213,"name":"Charanya Muralidharan","orcid":"0000-0002-4909-7056","position":1,"is_corresponding":false},{"id":348474,"name":"Saptarshi Roy","orcid":"0000-0002-4649-0741","position":2,"is_corresponding":false},{"id":396505,"name":"Justin J. Crowder","orcid":null,"position":3,"is_corresponding":false},{"id":417615,"name":"Jon D. Piganelli","orcid":"0000-0003-2699-9011","position":4,"is_corresponding":false},{"id":7382,"name":"Amelia K. Linnemann","orcid":"0000-0001-7356-4876","position":5,"is_corresponding":false},{"id":1369807,"name":"Matthew C. Austin","orcid":"0000-0002-8920-4311","position":0,"is_corresponding":true}],"reference_count":111,"raw_metadata":null,"created_at":"2026-07-19T02:47:55.918021Z","pmid":"39944686","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":[]}