{"doi":"10.64898/2025.12.19.695585","title":"PI3Kδ promotes T cell effector differentiation and plasticity during chronic infection","abstract":"Abstract Persistent antigen exposure in chronic infections and cancer leads to a progressive state of T cell dysfunction known as exhaustion, which represents a major barrier to effective immune control, but allows antigen-specific T cells to persist. Understanding signaling pathways that mitigate exhaustion and reinvigorate CD8 + T cell effector function is a key goal for immunotherapeutic strategies. Here, we show that an activating mutant of phosphoinositide-3-kinase δ (PI3Kδ) led to a reduction of FoxO1-dependent TCF-1 + stem-like progenitor CD8 + T cells that are required for sustaining antigen-specific T cells in response to chronic viral infection. Nonetheless, mice expressing activated PI3Kδ maintained CD8 + T cell responses that were skewed instead towards effector-like cells in a FoxO1-independent manner, associated with an amplified IL-21-STAT3 response axis and improved viral control. Activated PI3Kδ limited TOX expression, prevented epigenetic changes associated with T cell exhaustion, and promoted effector differentiation and function from both progenitor stem-like cells and cells with an exhausted phenotype. Together, this work uncovers a key role for PI3Kδ activation in shaping the balance and plasticity between effector function and exhaustion while promoting T cell persistence during chronic infection, providing insight for immunotherapeutic strategies.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":586808,"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":0.9528,"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":675995,"name":"Jennifer L. Cannons","orcid":null,"position":1,"is_corresponding":false},{"id":673841,"name":"Dominic P. Golec","orcid":"0000-0002-2741-3302","position":2,"is_corresponding":false},{"id":675996,"name":"Julie Reilley","orcid":null,"position":3,"is_corresponding":false},{"id":883306,"name":"Dan Corral","orcid":"0000-0002-0297-4349","position":4,"is_corresponding":false},{"id":990202,"name":"Eduard Ansaldo","orcid":"0000-0002-7128-3373","position":5,"is_corresponding":false},{"id":384765,"name":"Qin Xu","orcid":"0000-0002-7772-9444","position":6,"is_corresponding":false},{"id":1209467,"name":"Subrata Paul","orcid":"0000-0002-4482-3338","position":7,"is_corresponding":false},{"id":956701,"name":"Paul Schaughency","orcid":"0000-0002-3358-2102","position":8,"is_corresponding":false},{"id":1501884,"name":"Francisco P Otaizo-Carrasquero","orcid":null,"position":9,"is_corresponding":false},{"id":42912,"name":"Stacie M. Anderson","orcid":null,"position":10,"is_corresponding":false},{"id":1317948,"name":"Anshu Deewan","orcid":"0000-0002-0288-8926","position":11,"is_corresponding":false},{"id":235863,"name":"Dorian B. McGavern","orcid":"0000-0001-9568-545X","position":12,"is_corresponding":false},{"id":1019377,"name":"Pamela L Schwartzberg","orcid":"0000-0002-0817-3657","position":13,"is_corresponding":false},{"id":1501883,"name":"Andrea Charlotte Pichler","orcid":null,"position":0,"is_corresponding":true}],"reference_count":87,"raw_metadata":null,"created_at":"2026-07-19T02:59:32.191237Z","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":[]}