{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T01:42:05Z","timestamp":1792460525689,"version":"4.5.0"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T00:00:00Z","timestamp":1779235200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003478","name":"Ministry of Health, Labour and Welfare","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003478","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    X-linked adrenoleukodystrophy (X-ALD) is driven by ABCD1 dysfunction, causing very-long-chain fatty acid (VLCFA) accumulation and cerebral inflammation, yet the role of T cells in X-ALD remains unclear. Here, we show that\n                    <jats:italic>Abcd1<\/jats:italic>\n                    -deficient CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells exhibit a strong Th1 bias, producing more IFN-\u03b3 and less IL-10 under antigen-specific immunization\n                    <jats:italic>in vivo<\/jats:italic>\n                    and Th1-polarizing conditions\n                    <jats:italic>in vitro<\/jats:italic>\n                    . Transcriptional profiling revealed early induction of\n                    <jats:italic>Ifng<\/jats:italic>\n                    and\n                    <jats:italic>Tbx21<\/jats:italic>\n                    (T-bet) and late repression of\n                    <jats:italic>Prdm1<\/jats:italic>\n                    (Blimp-1), indicating Blimp-1\u2013dependent derepression of IFN-\u03b3 and reduced IL-10. Mechanistically, liver X receptor (LXR) signaling was markedly amplified, evidenced by upregulation of\n                    <jats:italic>Abca1<\/jats:italic>\n                    ,\n                    <jats:italic>Srebf1<\/jats:italic>\n                    , and the oxysterol 25-hydroxycholesterol (25-HC), driven by increased\n                    <jats:italic>Ch25h<\/jats:italic>\n                    . Pharmacological modulation validated this axis: the LXR antagonist SR9238 restored Blimp-1 and IL-10 while reducing IFN-\u03b3, whereas the LXR agonist T0901317 and exogenous 25-HC recapitulated the\n                    <jats:italic>Abcd1<\/jats:italic>\n                    -deficient phenotype. Thus, 25-HC\u2013LXR signaling suppresses Blimp-1, enforcing Th1 polarization in\n                    <jats:italic>Abcd1<\/jats:italic>\n                    -deficient CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells. These findings define an immunometabolic link between peroxisomal lipid metabolism and T cell differentiation and highlight the 25-HC\u2013LXR\u2013Blimp-1 axis as a mechanistic link regulating CD4\n                    <jats:sup>+<\/jats:sup>\n                    T\u2212cell polarization, with potential relevance to X-ALD\u2013associated neuroinflammation.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1722647","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T05:49:04Z","timestamp":1779256144000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Peroxisomal ABCD1 deficiency in mice drives Th1 bias through 25-HC\u2013LXR signaling in CD4+ T cells"],"prefix":"10.3389","volume":"17","author":[{"given":"Reina","family":"Maeda","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Cell Biology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama","place":["Toyama, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayu","family":"Oishi","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Cell Biology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama","place":["Toyama, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryutaro","family":"Nagamori","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Cell Biology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama","place":["Toyama, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mari","family":"Hikosaka-Kuniishi","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Cell Biology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama","place":["Toyama, 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