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Mitchell Endowed Fellowship of the Academic Programs Office"],"award-info":[{"award-number":["George J. Mitchell Endowed Fellowship of the Academic Programs Office"]}],"id":[{"id":"10.13039\/100007737","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2026,6,19]]},"abstract":"<jats:p>\n                    Peripheral tolerance depends on limiting conventional T cell responses to self-antigens. To define the contribution of nutritional factors and related epigenetic regulation, we perform in vivo CRISPR screening and identify the ascorbate transporter Slc23a2 as a key regulator of naive T cell (Tn) reactivity. T cell\u2013specific loss of\n                    <jats:italic toggle=\"yes\">Slc23a2<\/jats:italic>\n                    reduces intracellular ascorbate, induces regional DNA hypermethylation, enhances differentiation of Tn cells into effector and memory populations, and promotes low-grade autoimmune inflammation. These phenotypes mirror those caused by ascorbate deprivation,\n                    <jats:italic toggle=\"yes\">TET<\/jats:italic>\n                    dioxygenase deficiency, and aging. Mechanistically, Slc23a2 maintains TET enzymatic activity through ascorbate, dampens proximal TCR signaling, represses helper T cell lineage programs, and sustains Tcf1 expression and chromatin binding in Tn cells. Deletion of\n                    <jats:italic toggle=\"yes\">Tcf7<\/jats:italic>\n                    partially phenocopies\n                    <jats:italic toggle=\"yes\">Slc23a2<\/jats:italic>\n                    deficiency, whereas Tcf1 overexpression mitigates the effects. Together, these findings identify ascorbate and TET-dependent DNA demethylation as a checkpoint that restrains Tn cell reactivity to self-antigens, thereby maintaining peripheral tolerance, a process compromised with aging.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aeh1439","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T18:00:26Z","timestamp":1781719226000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Control of naive T cell reactivity and peripheral tolerance by ascorbate and TET activity"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3413-2338","authenticated-orcid":true,"given":"Xiaolei","family":"Hao","sequence":"first","affiliation":[{"name":"Department of Immunology, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105, 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