{"id":"f376ca6b-cd1f-5a2c-9978-6a7fa80528e5","stable_key":"research:tfh-gpx4","predicate":"supports","statement":"GPX4 protects follicular helper T cells from ferroptosis in the studied T-cell-specific models.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"literature_reviewed:direct_experimental","direction":"positive","is_public":true,"mechanism_event_id":"5411f147-234e-58e5-85eb-d932042d1a10","mechanism_event_label":"Protection of helper T cells is a distinct route to supporting antibody responses.","subject":{"id":"e9bb13ee-f238-51e6-9101-78ddfd11465c","slug":"gpx4","display_name":"GPX4","entity_type_key":"protein"},"object":{"id":"e229215d-5139-5b24-97b8-aa72aaf511ad","slug":"tfh-survival","display_name":"follicular helper T-cell survival","entity_type_key":"cellular_process"},"evidence_count":1,"mechanism_event":{"id":"5411f147-234e-58e5-85eb-d932042d1a10","stable_key":"research:tfh-gpx4","event_type":"contextual_mechanism","label":"Protection of helper T cells is a distinct route to supporting antibody responses.","description":"GPX4 protects follicular helper T cells from ferroptosis in the studied T-cell-specific models.","status":"active","compartment":null,"participants":[{"entity":{"id":"e9bb13ee-f238-51e6-9101-78ddfd11465c","slug":"gpx4","display_name":"GPX4","entity_type_key":"protein"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"e229215d-5139-5b24-97b8-aa72aaf511ad","slug":"tfh-survival","display_name":"follicular helper T-cell survival","entity_type_key":"cellular_process"},"role":"object","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""}]},"contexts":[{"dimension":"cell_type","value_text":"Follicular helper T cells","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Mouse T-cell/Tfh experiments and young-adult influenza vaccination study","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"Not B-cell-intrinsic or proof of all vaccine effects; interpret corrected article.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"organism","value_text":"Mus musculus","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"5781de10-9cea-58a7-9bad-414353d7d433","evidence_kind":"curated_literature_summary","locator":"lines 1348-1358","start_line":1348,"end_line":1358,"excerpt":"## tfh-gpx4\n\nProtection of helper T cells is a distinct route to supporting antibody responses.\n\nGPX4 protects follicular helper T cells from ferroptosis in the studied T-cell-specific models.\n\nOrganism: Mus musculus\nCell type: Follicular helper T cells\nExperimental model: Mouse T-cell/Tfh experiments and young-adult influenza vaccination study\nLimitations: Not B-cell-intrinsic or proof of all vaccine effects; interpret corrected article.\nPrimary reference: [Selenium-GPX4 axis protects follicular helper T cells from ferroptosis](https://www.nature.com/articles/s41590-021-00996-0)","model_system":"Mouse T-cell/Tfh experiments and young-adult influenza vaccination study","directness":"author_interpretation","verification_status":"secondary_verified","notes":"Curated summary; inspect the linked primary papers for original methods and results.","relationship":"supports","weight":1.0,"link_notes":"","source":{"id":"4f892f13-06ea-5199-a33c-a703f35c80ae","stable_key":"selenium-research-2026-09-17","title":"Selenium: literature corrections and mechanism additions","document_type":"curated_literature_review","citation_label":"Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually","file_path":"","sha256":"0b818b10c1c7120e5caf7f4d4019d7bd025d745692e424f515d3ef903c9ab7f3","revision_id":"80984e03-5f0f-5877-8094-afef7637444e","review_status":"secondary_verified","notes":"Secondary curated summaries of primary experiments, with explicit models and limitations. Not archived primary full text."}}],"relations":[],"conflicts":[],"corrections":[{"id":"97c1d4e9-b4c5-5a64-95ce-f9dc60e9d1c0","title":"GPX4 dependence differs between B-cell subsets and Tfh cells","kind":"contradiction","status":"corrected","why":"B-cell-specific deletion preserved measured B2/germinal-center responses while harming B1/MZ; a Tfh phenotype cannot be assigned to germinal-center B cells.","resolution":"Separate lineage-specific findings; do not infer nutritional deletion of an immune compartment in humans.","created_at":"2026-09-17 07:19:34","record_type":"correction","display_label":"Correction history","record_url":"/corrections/97c1d4e9-b4c5-5a64-95ce-f9dc60e9d1c0","literature_review":{"revision_id":"80984e03-5f0f-5877-8094-afef7637444e","start_line":1630,"end_line":1636,"papers":[{"paper_key":"muri-b-2019","title":"B1 and Marginal Zone B Cells but Not Follicular B2 Cells Require Gpx4 to Prevent Lipid Peroxidation and Ferroptosis","url":"https://pubmed.ncbi.nlm.nih.gov/31775041/","doi":"10.1016/j.celrep.2019.10.070","year":2019,"model":"Mouse B-cell-specific Gpx4 deletion","summary":"B1/MZ vulnerable; measured follicular B2 and germinal-center responses preserved."},{"paper_key":"yao-2021","title":"Selenium-GPX4 axis protects follicular helper T cells from ferroptosis","url":"https://www.nature.com/articles/s41590-021-00996-0","doi":"10.1038/s41590-021-00996-0","year":2021,"model":"Mouse T-cell/Tfh experiments and young-adult influenza vaccination study","summary":"Narrow Tfh protection mechanism; use corrected article, author correction DOI 10.1038/s41590-024-01949-z is metadata/FACS correction, not retraction."}]},"sides":[{"conflict_id":"97c1d4e9-b4c5-5a64-95ce-f9dc60e9d1c0","ordinal":0,"label":"Original preserved statement","revision_id":"fbed30e0-1c0d-5b83-8a1f-2867fbe8a5b5","start_line":137,"end_line":137,"quote":"| **Germinal center B**                     | lost → no affinity maturation                                              | vitamin E                            |","claim_id":null,"source_key":"immune","source_title":"Selenium in immune cells","claim_ids":[]},{"conflict_id":"97c1d4e9-b4c5-5a64-95ce-f9dc60e9d1c0","ordinal":1,"label":"Original preserved statement","revision_id":"fbed30e0-1c0d-5b83-8a1f-2867fbe8a5b5","start_line":158,"end_line":158,"quote":"**Selenium deficiency silently deletes an entire arm of innate humoral immunity**, and nothing in a standard immune workup would show it.","claim_id":null,"source_key":"immune","source_title":"Selenium in immune cells","claim_ids":[]},{"conflict_id":"97c1d4e9-b4c5-5a64-95ce-f9dc60e9d1c0","ordinal":2,"label":"Original preserved statement","revision_id":"f8f97804-c1fb-56df-9c06-c02e36e2a5b8","start_line":350,"end_line":394,"quote":"Much of the detailed cell-by-cell mechanism comes from animal and cell models. These findings are biologically important but should not be converted directly into plasma cutoffs or guaranteed clinical outcomes.\n\nImmune component\n\nExperimental finding\n\nEvidence level\n\nT-cell subsets\n\nGPX4-dependent control of lipid peroxidation can affect survival and differentiation\n\nCell/animal\n\nCD8 effector responses\n\nRedox and lipid-peroxidation defenses can affect expansion/function\n\nCell/animal\n\nB-cell compartments\n\nSelenium-dependent redox systems can influence antibody responses\n\nMostly animal; some human supplementation data\n\nNeutrophils\n\nOxidative-burst biology creates high antioxidant demand\n\nCell/animal\n\nNK activity\n\nSelenium status has been associated with altered activity in some studies\n\nHuman/animal, heterogeneous\n\nMacrophage / inflammasome signaling\n\nThioredoxin, TXNIP, lipid peroxide and eicosanoid pathways provide plausible mechanisms\n\nCell/animal\n\nA useful summary is: selenium status can alter immune redox tone and cell survival, but no single immune-cell cascade explains all reported supplementation effects.","claim_id":null,"source_key":"deficiency","source_title":"Selenium deficiency: a mechanism-first reference","claim_ids":[]},{"conflict_id":"97c1d4e9-b4c5-5a64-95ce-f9dc60e9d1c0","ordinal":3,"label":"Literature correction and experimental limits","revision_id":"80984e03-5f0f-5877-8094-afef7637444e","start_line":1630,"end_line":1636,"quote":"## GPX4 dependence differs between B-cell subsets and Tfh cells\n\nB-cell-specific deletion preserved measured B2/germinal-center responses while harming B1/MZ; a Tfh phenotype cannot be assigned to germinal-center B cells.\n\nSeparate lineage-specific findings; do not infer nutritional deletion of an immune compartment in humans.\nPrimary reference: [B1 and Marginal Zone B Cells but Not Follicular B2 Cells Require Gpx4 to Prevent Lipid Peroxidation and Ferroptosis](https://pubmed.ncbi.nlm.nih.gov/31775041/)\nPrimary reference: [Selenium-GPX4 axis protects follicular helper T cells from ferroptosis](https://www.nature.com/articles/s41590-021-00996-0)","claim_id":null,"source_key":"selenium-research-2026-09-17","source_title":"Selenium: literature corrections and mechanism additions","claim_ids":[]}]},{"id":"34f4e373-09c8-5971-b0c3-2fefbfa43b73","title":"GPX4–Tfh protection does not explain every vaccine association","kind":"qualification","status":"qualified","why":"Mouse mechanism and young-adult influenza results do not establish one threshold mediating every vaccine response; IL-2 can oppose Tfh differentiation.","resolution":"Keep candidate mechanism and corrected article; retain later rejection of one cascade and independent IL-2/STAT5/Blimp-1 branch.","created_at":"2026-09-17 07:19:34","record_type":"qualification","display_label":"Source qualification","record_url":"/corrections/34f4e373-09c8-5971-b0c3-2fefbfa43b73","literature_review":{"revision_id":"80984e03-5f0f-5877-8094-afef7637444e","start_line":1638,"end_line":1644,"papers":[{"paper_key":"yao-2021","title":"Selenium-GPX4 axis protects follicular helper T cells from ferroptosis","url":"https://www.nature.com/articles/s41590-021-00996-0","doi":"10.1038/s41590-021-00996-0","year":2021,"model":"Mouse T-cell/Tfh experiments and young-adult influenza vaccination study","summary":"Narrow Tfh protection mechanism; use corrected article, author correction DOI 10.1038/s41590-024-01949-z is metadata/FACS correction, not retraction."},{"paper_key":"johnston-2012-stat5-tfh","title":"STAT5 is a potent negative regulator of TFH cell differentiation","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC3281266/","doi":"10.1084/jem.20111174","year":2012,"model":"Mouse LCMV infection, transferred antigen-specific CD4 cells and genetic perturbations","summary":"Tests IL-2/STAT5 suppression of Tfh differentiation and its dependence on Blimp-1."}]},"sides":[{"conflict_id":"34f4e373-09c8-5971-b0c3-2fefbfa43b73","ordinal":0,"label":"Original preserved statement","revision_id":"fbed30e0-1c0d-5b83-8a1f-2867fbe8a5b5","start_line":152,"end_line":152,"quote":"**Tfh are the selenium-sensitive bottleneck of the humoral response.** Selenium supplementation increases Tfh numbers and antibody titers. Every \"selenium improves antibody response to vaccination\" epidemiology paper is downstream of **one lipid peroxidation threshold in one T cell subset.**","claim_id":null,"source_key":"immune","source_title":"Selenium in immune cells","claim_ids":[]},{"conflict_id":"34f4e373-09c8-5971-b0c3-2fefbfa43b73","ordinal":1,"label":"Original preserved statement","revision_id":"f8f97804-c1fb-56df-9c06-c02e36e2a5b8","start_line":394,"end_line":394,"quote":"A useful summary is: selenium status can alter immune redox tone and cell survival, but no single immune-cell cascade explains all reported supplementation effects.","claim_id":null,"source_key":"deficiency","source_title":"Selenium deficiency: a mechanism-first reference","claim_ids":[]},{"conflict_id":"34f4e373-09c8-5971-b0c3-2fefbfa43b73","ordinal":2,"label":"Literature correction and experimental limits","revision_id":"80984e03-5f0f-5877-8094-afef7637444e","start_line":1638,"end_line":1644,"quote":"## GPX4–Tfh protection does not explain every vaccine association\n\nMouse mechanism and young-adult influenza results do not establish one threshold mediating every vaccine response; IL-2 can oppose Tfh differentiation.\n\nKeep candidate mechanism and corrected article; retain later rejection of one cascade and independent IL-2/STAT5/Blimp-1 branch.\nPrimary reference: [Selenium-GPX4 axis protects follicular helper T cells from ferroptosis](https://www.nature.com/articles/s41590-021-00996-0)\nPrimary reference: [STAT5 is a potent negative regulator of TFH cell differentiation](https://pmc.ncbi.nlm.nih.gov/articles/PMC3281266/)","claim_id":null,"source_key":"selenium-research-2026-09-17","source_title":"Selenium: literature corrections and mechanism additions","claim_ids":[]}]}],"research":{"topic":"Selenium scientific audit","plain_language":"Protection of helper T cells is a distinct route to supporting antibody responses.","evidence_scope":"direct_experimental","papers":[{"key":"yao-2021","title":"Selenium-GPX4 axis protects follicular helper T cells from ferroptosis","url":"https://www.nature.com/articles/s41590-021-00996-0","doi":"10.1038/s41590-021-00996-0","year":2021,"model":"Mouse T-cell/Tfh experiments and young-adult influenza vaccination study","summary":"Narrow Tfh protection mechanism; use corrected article, author correction DOI 10.1038/s41590-024-01949-z is metadata/FACS correction, not retraction."}]}}