{"doi":"10.1101/2022.06.02.494443","title":"Deletion of CD226 in Foxp3 <sup>+</sup> T cells Reduces Diabetes Incidence in Non-Obese Diabetic Mice by Improving Regulatory T Cell Stability and Function","abstract":"Abstract Co-stimulation serves as a critical checkpoint for T cell development and activation, and several genetic variants affecting co-stimulatory pathways confer risk for autoimmune diseases. A single nucleotide polymorphism in CD226 ( rs763361 ; G307S) has been shown to increase susceptibility to type 1 diabetes, multiple sclerosis, and rheumatoid arthritis. CD226 competes with the co-inhibitory receptor TIGIT (T cell immunoreceptor with Ig and ITIM domains) to bind CD155 to amplify TCR signaling. We previously found that Cd226 knockout protected non-obese diabetic (NOD) mice from disease, but the impact of CD226 signaling on individual immune subsets remained unclear. We focused on regulatory T cells (Tregs) as a population of interest, as prior reports demonstrated that human CD226 + Tregs exhibit reduced FOXP3 + Helios + purity and suppressive function following expansion. Hence, we hypothesized that global deletion of Cd226 would increase Treg stability and accordingly, Treg-specific Cd226 deletion would inhibit diabetes in NOD mice. Indeed, crossing the NOD. Cd226 -/- and NOD. Foxp3 -GFP-Cre. R26 -loxP-STOP-loxP-YFP Treg-fate tracking strains resulted in increased Treg induction and decreased FoxP3-deficient “ex-Tregs” in the pancreatic lymph nodes. We generated a Treg-conditional knockout (Treg Δ Cd226 ) strain and found that female Treg Δ Cd226 mice had decreased insulitis and diabetes incidence compared to Treg WT mice. Additionally, we observed increased TIGIT expression on Tregs and conventional CD4 + T cells within the pancreas of Treg Δ Cd226 versus Treg WT mice. These findings demonstrate that an imbalance of CD226/TIGIT signaling may contribute to Treg destabilization in the NOD mouse and highlight the potential for therapeutic targeting of this pathway to prevent or reverse autoimmunity.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":308987,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9554,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":729988,"name":"Matthew E. Brown","orcid":"0000-0001-8230-5243","position":1,"is_corresponding":false},{"id":880165,"name":"Lindsey K. Sachs","orcid":null,"position":2,"is_corresponding":false},{"id":879423,"name":"Juan M. Arnoletti","orcid":"0000-0002-1313-8725","position":3,"is_corresponding":false},{"id":479038,"name":"Wen-I Yeh","orcid":"0000-0002-5705-4232","position":4,"is_corresponding":false},{"id":251267,"name":"Amanda L. Posgai","orcid":"0000-0002-9491-0958","position":5,"is_corresponding":false},{"id":479037,"name":"Melanie R. Shapiro","orcid":"0000-0003-2090-0877","position":6,"is_corresponding":false},{"id":256321,"name":"Yi‐Guang Chen","orcid":"0000-0002-1741-9719","position":7,"is_corresponding":false},{"id":356521,"name":"Todd M. Brusko","orcid":"0000-0003-2878-9296","position":8,"is_corresponding":false},{"id":678329,"name":"Puchong Thirawatananond","orcid":"0000-0003-4973-7380","position":0,"is_corresponding":true}],"reference_count":37,"raw_metadata":null,"created_at":"2026-07-19T00:33:07.132912Z","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":[]}