{"doi":"10.4049/jimmunol.2200407","title":"STAT1 Controls the Functionality of Influenza-Primed CD4 T Cells but Therapeutic STAT4 Engagement Maximizes Their Antiviral Impact","abstract":"It is generally accepted that influenza A virus (IAV) infection promotes a Th1-like CD4 T cell response and that this effector program underlies its protective impact. Canonical Th1 polarization requires cytokine-mediated activation of the transcription factors STAT1 and STAT4 that synergize to maximize the induction of the \"master regulator\" Th1 transcription factor, T-bet. Here, we determine the individual requirements for these transcription factors in directing the Th1 imprint primed by influenza infection in mice by tracking virus-specific wild-type or T-bet-deficient CD4 T cells in which STAT1 or STAT4 is knocked out. We find that STAT1 is required to protect influenza-primed CD4 T cells from NK cell-mediated deletion and for their expression of hallmark Th1 attributes. STAT1 is also required to prevent type I IFN signals from inhibiting the induction of the Th17 master regulator, Rorγt, in Th17-prone T-bet-/- cells responding to IAV. In contrast, STAT4 expression does not appreciably impact the phenotypic or functional attributes of wild-type or T-bet-/- CD4 T cell responses. However, cytokine-mediated STAT4 activation in virus-specific CD4 T cells enhances their Th1 identity in a T-bet-dependent manner, indicating that influenza infection does not promote maximal Th1 induction. Finally, we show that the T-bet-dependent protective capacity of CD4 T cell effectors against IAV is optimized by engaging both STAT1 and STAT4 during Th1 priming, with important implications for vaccine strategies aiming to generate T cell immunity.","journal":"The Journal of Immunology","year":2023,"id":363712,"datarank":0.31191623125197543,"base_score":2.0794415416798357,"endowment":2.0794415416798357,"self_citation_contribution":0.31191623125197543,"citation_network_contribution":0.0,"self_endowment_contribution":0.31191623125197543,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9501,"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":925797,"name":"Kunal Dhume","orcid":"0000-0003-1317-2795","position":1,"is_corresponding":false},{"id":1118137,"name":"Emily Prokop","orcid":"0000-0001-8843-7773","position":2,"is_corresponding":false},{"id":807092,"name":"Tara M. Strutt","orcid":"0000-0002-4465-1783","position":3,"is_corresponding":false},{"id":807093,"name":"K. Kai McKinstry","orcid":"0000-0002-5038-7229","position":4,"is_corresponding":false},{"id":1118136,"name":"Caroline Finn","orcid":"0000-0003-4809-132X","position":0,"is_corresponding":true}],"reference_count":73,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:14:32.510714Z","pmid":"36961447","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":[]}