{"doi":"10.17615/x1ay-6m51","title":"Innate PI3K p110  Regulates Th1/Th17 Development and Microbiota-Dependent Colitis","abstract":"The p110δ subunit of class IA PI3K modulates signaling in innate immune cells. We previously demonstrated that mice harboring a kinase-dead p110δ subunit (p110δ(KD)) develop spontaneous colitis. Macrophages contributed to the Th1/Th17 cytokine bias in p110δ(KD) mice through increased IL-12 and IL-23 expression. In this study, we show that the enteric microbiota is required for colitis development in germfree p110δ(KD) mice. Colonic tissue and macrophages from p110δ(KD) mice produce significantly less IL-10 compared with wild-type mice. p110δ(KD) APCs cocultured with naive CD4+ Ag-specific T cells also produce significantly less IL-10 and induce more IFN-γ- and IL-17A-producing CD4+ T cells compared with wild-type APCs. Illustrating the importance of APC-T cell interactions in colitis pathogenesis in vivo, Rag1(-/-)/p110δ(KD) mice develop mild colonic inflammation and produced more colonic IL-12p40 compared with Rag1(-/-) mice. However, CD4+ CD45RB(high/low) T cell Rag1(-/-)/p110δ(KD) recipient mice develop severe colitis with increased percentages of IFN-γ- and IL-17A-producing lamina propria CD3+D4+ T cells compared with Rag1(-/-) recipient mice. Intestinal tissue samples from patients with Crohn's disease reveal significantly lower expression of PIK3CD compared with intestinal samples from non-inflammatory bowel disease control subjects (p < 0.05). PIK3CD expression inversely correlates with the ratio of IL12B:IL10 expression. In conclusion, the PI3K subunit p110δ controls homeostatic APC-T cell interactions by altering the balance between IL-10 and IL-12/23. Defects in p110δ expression and/or function may underlie the pathogenesis of human inflammatory bowel disease and lead to new therapeutic strategies.","journal":"UNC Libraries","year":2020,"id":117357,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9487,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":545083,"name":"Steven M. Russo","orcid":null,"position":1,"is_corresponding":false},{"id":87733,"name":"Scott E. Plevy","orcid":null,"position":2,"is_corresponding":false},{"id":36349,"name":"R. Balfour Sartor","orcid":"0000-0002-7820-632X","position":3,"is_corresponding":false},{"id":546954,"name":"Bo Liu","orcid":"0009-0005-6182-8172","position":4,"is_corresponding":false},{"id":307850,"name":"Gregory R. Gipson","orcid":"0000-0002-3698-4182","position":5,"is_corresponding":false},{"id":378413,"name":"Luke B. Borst","orcid":"0000-0002-2736-1960","position":6,"is_corresponding":false},{"id":299129,"name":"Jenny P.‐Y. Ting","orcid":"0000-0002-7846-0395","position":7,"is_corresponding":false},{"id":233525,"name":"Hans Herfarth","orcid":"0000-0003-4268-823X","position":8,"is_corresponding":false},{"id":525087,"name":"Shehzad Z. Sheikh","orcid":"0000-0002-4238-3674","position":9,"is_corresponding":false},{"id":547717,"name":"Jennifer K. Uno","orcid":null,"position":10,"is_corresponding":false},{"id":546955,"name":"Yoshiyuki Mishima","orcid":"0000-0001-5261-6411","position":11,"is_corresponding":false},{"id":525088,"name":"Erin C. Steinbach","orcid":"0000-0002-6165-8928","position":12,"is_corresponding":false},{"id":250789,"name":"Taku Kobayashi","orcid":"0000-0002-2073-4234","position":13,"is_corresponding":false},{"id":547716,"name":"Samantha T. Kennedy","orcid":null,"position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-18T23:13:51.309289Z","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":[]}