{"doi":"10.1126/sciadv.adc9657","title":"Phosphofructokinase P fine-tunes T regulatory cell metabolism, function, and stability in systemic autoimmunity","abstract":"<jats:p>\n                    Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by defective regulatory T (T\n                    <jats:sub>reg</jats:sub>\n                    ) cells. Here, we demonstrate that a T cell–specific deletion of calcium/calmodulin-dependent protein kinase 4 (CaMK4) improves disease in B6.\n                    <jats:italic>lpr</jats:italic>\n                    lupus-prone mice and expands T\n                    <jats:sub>reg</jats:sub>\n                    cells. Mechanistically, CaMK4 phosphorylates the glycolysis rate-limiting enzyme 6-phosphofructokinase, platelet type (PFKP) and promotes aerobic glycolysis, while its end product fructose-1,6-biphosphate suppresses oxidative metabolism. In T\n                    <jats:sub>reg</jats:sub>\n                    cells, a CRISPR-Cas9–enabled\n                    <jats:italic>Pfkp</jats:italic>\n                    deletion recapitulated the metabolism of\n                    <jats:italic>Camk4</jats:italic>\n                    <jats:sup>−/−</jats:sup>\n                    T\n                    <jats:sub>reg</jats:sub>\n                    cells and improved their function and stability in vitro and in vivo. In SLE CD4\n                    <jats:sup>+</jats:sup>\n                    T cells, PFKP enzymatic activity correlated with SLE disease activity and pharmacologic inhibition of CaMK4-normalized PFKP activity, leading to enhanced T\n                    <jats:sub>reg</jats:sub>\n                    cell function. In conclusion, we provide molecular insights in the defective metabolism and function of T\n                    <jats:sub>reg</jats:sub>\n                    cells in SLE and identify PFKP as a target to fine-tune T\n                    <jats:sub>reg</jats:sub>\n                    cell metabolism and thereby restore their function.\n                  </jats:p>","journal":"Science Advances","year":2022,"id":686978,"datarank":0.6090664515819629,"base_score":4.060443010546419,"endowment":4.060443010546419,"self_citation_contribution":0.6090664515819629,"citation_network_contribution":0.0,"self_endowment_contribution":0.6090664515819629,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":57,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":387834,"name":"Wenliang Pan","orcid":"0009-0003-5965-2126","position":1,"is_corresponding":false},{"id":738808,"name":"Ryo Hisada","orcid":"0000-0002-4225-1639","position":2,"is_corresponding":false},{"id":766551,"name":"Afroditi Boulougoura","orcid":"0000-0002-0161-3322","position":3,"is_corresponding":false},{"id":693151,"name":"Nobuya Yoshida","orcid":null,"position":4,"is_corresponding":false},{"id":1794712,"name":"Milena Vukelic","orcid":null,"position":5,"is_corresponding":false},{"id":905092,"name":"Masataka Umeda","orcid":"0000-0002-6647-7130","position":6,"is_corresponding":false},{"id":257240,"name":"Suzanne Krishfield","orcid":null,"position":7,"is_corresponding":false},{"id":281388,"name":"Maria Tsokos","orcid":"0000-0001-8072-1358","position":8,"is_corresponding":false},{"id":12823,"name":"George C. Tsokos","orcid":"0000-0001-9589-2360","position":9,"is_corresponding":false},{"id":443111,"name":"Marc Scherlinger","orcid":"0000-0002-9453-5895","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Phosphofructokinase P fine-tunes T regulatory cell metabolism, function, and stability in systemic autoimmunity","abstract":"<jats:p>\n                    Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by defective regulatory T (T\n                    <jats:sub>reg</jats:sub>\n                    ) cells. Here, we demonstrate that a T cell–specific deletion of calcium/calmodulin-dependent protein kinase 4 (CaMK4) improves disease in B6.\n                    <jats:italic>lpr</jats:italic>\n                    lupus-prone mice and expands T\n                    <jats:sub>reg</jats:sub>\n                    cells. Mechanistically, CaMK4 phosphorylates the glycolysis rate-limiting enzyme 6-phosphofructokinase, platelet type (PFKP) and promotes aerobic glycolysis, while its end product fructose-1,6-biphosphate suppresses oxidative metabolism. In T\n                    <jats:sub>reg</jats:sub>\n                    cells, a CRISPR-Cas9–enabled\n                    <jats:italic>Pfkp</jats:italic>\n                    deletion recapitulated the metabolism of\n                    <jats:italic>Camk4</jats:italic>\n                    <jats:sup>−/−</jats:sup>\n                    T\n                    <jats:sub>reg</jats:sub>\n                    cells and improved their function and stability in vitro and in vivo. In SLE CD4\n                    <jats:sup>+</jats:sup>\n                    T cells, PFKP enzymatic activity correlated with SLE disease activity and pharmacologic inhibition of CaMK4-normalized PFKP activity, leading to enhanced T\n                    <jats:sub>reg</jats:sub>\n                    cell function. In conclusion, we provide molecular insights in the defective metabolism and function of T\n                    <jats:sub>reg</jats:sub>\n                    cells in SLE and identify PFKP as a target to fine-tune T\n                    <jats:sub>reg</jats:sub>\n                    cell metabolism and thereby restore their function.\n                  </jats:p>","is_dataset_classified":null,"base_score":4.060443010546419,"endowment":4.060443010546419,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"36449620","pmcid":"PMC9710877","openalex_id":"https://openalex.org/W4310437404","authors":[],"funders":[{"funder_name":"NIAID NIH HHS","grant_id":"R37 AI049954","title":null},{"funder_name":"National Institutes of Health","grant_id":"5R37AI049954-18","title":"Gene transcription in SLE"}],"total_grants":2,"fwci":3.8533,"citation_percentile":0.94922049,"influential_citations":0,"citation_trend":[{"year":2023,"count":9},{"year":2024,"count":20},{"year":2025,"count":15},{"year":2026,"count":13}],"oa_status":"gold","license":"cc-by-nc","oa_locations":[{"url":"https://doi.org/10.1126/sciadv.adc9657","host_type":"journal"},{"url":"https://doi.org/10.1126/sciadv.adc9657","host_type":"publisher"},{"url":"https://www.science.org/doi/pdf/10.1126/sciadv.adc9657","host_type":"publisher"},{"url":"https://pubmed.ncbi.nlm.nih.gov/36449620","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/9710877","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC9710877","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC9710877?pdf=render","host_type":"Europe_PMC"},{"url":"http://dx.doi.org/10.1126/sciadv.adc9657","host_type":""}],"fields_of_study":["Immune Cell Function and Interaction","T-cell and B-cell Immunology","Diabetes and associated disorders","0301 basic medicine","03 medical and health sciences","Animals","Mice","Phosphofructokinases","Autoimmunity","T-Lymphocytes, Regulatory","Immunotherapy","Lupus Erythematosus, Systemic"],"mesh_terms":["Animals","Immunotherapy","Lupus Erythematosus, Systemic","Autoimmunity","Phosphofructokinases","T-Lymphocytes, Regulatory","Mice"],"keywords":["Glycolysis","Phosphofructokinase","Autoimmunity","Autoimmune disease","Biology","Kinase","Metabolism","Cell biology","Cancer research","Immunology","Biochemistry","Immune system","Antibody","Mice","Phosphofructokinases","Animals","Lupus Erythematosus, Systemic","Biomedicine and Life Sciences","Immunotherapy","T-Lymphocytes, Regulatory"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-18T21:01:23.261477Z","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":[]}