{"doi":"10.4049/jimmunol.2000672","title":"Functional Analysis of Immune Signature Genes in Th1* Memory Cells Links ISOC1 and Pyrimidine Metabolism to IFN-γ and IL-17 Production","abstract":"Abstract CCR6+CXCR3+CCR4−CD4+ memory T cells, termed Th1*, are important for long-term immunity to Mycobacterium tuberculosis and the pathogenesis of autoimmune diseases. Th1* cells express a unique set of lineage-specific transcription factors characteristic of both Th1 and Th17 cells and display distinct gene expression profiles compared with other CD4+ T cell subsets. To examine molecules and signaling pathways important for the effector function of Th1* cells, we performed loss-of-function screening of genes selectively enriched in the Th1* subset. The genetic screen yielded candidates whose depletion significantly impaired TCR-induced IFN-γ production. These included genes previously linked to IFN-γ or M. tuberculosis susceptibility and novel candidates, such as ISOC1, encoding a metabolic enzyme of unknown function in mammalian cells. ISOC1-depleted T cells, which produced less IFN-γ and IL-17, displayed defects in oxidative phosphorylation and glycolysis and impairment of pyrimidine metabolic pathway. Supplementation with extracellular pyrimidines rescued both bioenergetics and IFN-γ production in ISOC1-deficient T cells, indicating that pyrimidine metabolism is a key driver of effector functions in CD4+ T cells and Th1* cells. Results provide new insights into the immune-stimulatory function of ISOC1 as well as the particular metabolic requirements of human memory T cells, providing a novel resource for understanding long-term T cell–driven responses.","journal":"The Journal of Immunology","year":2021,"id":171440,"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":26,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9593,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":239474,"name":"Ian T. Mathews","orcid":"0000-0003-4773-7985","position":1,"is_corresponding":false},{"id":692643,"name":"Alexander Y. Andreyev","orcid":"0000-0002-9246-9943","position":2,"is_corresponding":false},{"id":706920,"name":"Gökmen Altay","orcid":null,"position":3,"is_corresponding":false},{"id":230241,"name":"Cecilia S. Lindestam Arlehamn","orcid":"0000-0001-7302-8002","position":4,"is_corresponding":false},{"id":110385,"name":"Pandurangan Vijayanand","orcid":"0000-0001-7067-9723","position":5,"is_corresponding":false},{"id":376926,"name":"Roland Nilsson","orcid":"0000-0002-6020-7498","position":6,"is_corresponding":false},{"id":233460,"name":"Mohit Jain","orcid":"0000-0001-8628-2069","position":7,"is_corresponding":false},{"id":55670,"name":"Alessandro Sette","orcid":"0000-0001-7013-2250","position":8,"is_corresponding":false},{"id":34766,"name":"Bjoern Peters","orcid":"0000-0002-8457-6693","position":9,"is_corresponding":false},{"id":246517,"name":"Sonia Sharma","orcid":"0000-0002-6556-1963","position":10,"is_corresponding":false},{"id":706145,"name":"Yulia Kushnareva","orcid":"0000-0002-1931-5390","position":0,"is_corresponding":true}],"reference_count":63,"raw_metadata":null,"created_at":"2026-07-18T23:46:33.067299Z","pmid":"33547171","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":[]}