{"doi":"10.4049/jimmunol.210.supp.77.03","title":"Lnk/Sh2b3 modulates bioenergetic metabolism of activated CD8 T cells and control the development of Type 1 Diabetes","abstract":"Abstract Recent genome-wide association studies (GWAS) have shown a strong correlation between a genetic polymorphism in the SH2B3 gene and the development of autoimmune diseases, including type 1 diabetes (T1D). Lnk/Sh2b3 is an adaptor protein interacting with various intracellular proteins involved in JAK/STAT cytokine signaling of different cell types, including CD8 T cells. Additionally, Sh2b3-deficient CD8 T cells are hypersensitive to IL-15 stimulation. However, how reduced Sh2b3 function affects the molecular mechanisms that activate and sustain CD8 T cells promoting T1D development remains elusive. We hypothesized that genetic deletion of Sh2b3 in the non-obese diabetic (NOD) mouse would impact T1D incidence by altering T cell activation. NOD. Sh2b3−/− mice developed diabetes faster than wild-type controls. Additionally, Sh2b3-deficient CD8 T cells were hyperresponsive to IL-15 stimulation, promoting the generation of the activated CD44 high CD8 T cell population. Intriguingly, IL-15-stimulated Sh2b3−/− splenocytes possessed significantly higher mitochondrial respiratory capacity (SRC) and ATP synthesis than the wild-type counterparts. Furthermore, CD8 T cells of NOD. Sh2b3−/− mice showed increased expression of genes associated with mitochondrial biogenesis and oxidative metabolisms in response to in vitro IL-15 stimulation. Overall, our study supports a role of Sh2b3 in T1D development by regulating mitochondrial biogenesis and metabolism of IL-15-stimulated CD8 T cell. Our study provides new insight into the role of Sh2b3 in activating and sustaining the CD8 T cell response in the pathogenesis of T1D. Funded by NIH DK097605 Funded by NIH DK097605","journal":"The Journal of Immunology","year":2023,"id":394923,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9502,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":378098,"name":"Bardees M. Foda","orcid":"0000-0001-8869-3697","position":1,"is_corresponding":false},{"id":286498,"name":"Aron M. Geurts","orcid":"0000-0002-4347-2505","position":2,"is_corresponding":false},{"id":256321,"name":"Yi‐Guang Chen","orcid":"0000-0002-1741-9719","position":3,"is_corresponding":false},{"id":698470,"name":"Tarun Pant","orcid":"0000-0003-2862-3923","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T01:19:18.686170Z","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":[]}