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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,10,27]]},"abstract":"<jats:p>\n                    Immune\u2013neuron interactions play a critical role in neuroinflammatory and neurodegenerative diseases, such as Alzheimer\u2019s disease (AD), but how CD8\u207a T cells contribute to brain pathology remains poorly understood. Amyloid-\u03b2 (A\u03b2), a hallmark of AD, is known to trigger neuronal stress and inflammation. Here, we established a human cortical organoid (hCO) model to investigate CD8\u207a T cell responses to A\u03b2-induced neurodegenerative stress. A\u03b2 exposure increased neuronal expression of CX3CL1 (fractalkine), which engages its receptor CX3CR1 on CD8\u207a T cells. Transwell migration assays showed enhanced recruitment of CX3CR1\u207a CD8\u207a T cells toward A\u03b2-treated hCOs. In parallel, A\u03b2 upregulated IL-15 expression, a cytokine that supports CD8\u207a T cell activation. The infiltration of CD8\u207a T cells led to neuronal injury, marked by MAP2 loss and cleaved Caspase-3 activation, accompanied by an increase in gene signatures for cell death and inflammation. Exposure to the conditioned medium of activated CX3CR1\n                    <jats:sup>high<\/jats:sup>\n                    CD8\u207a T cell recapitulated this damage, and the neutralization of CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell cytokines and cytotoxic molecules rescued the phenotype. These findings identify the CX3CL1\u2013CX3CR1 axis and CD8\u207a T cell effector programs as drivers of neurotoxicity and establish brain organoids as a platform to study immune-driven neurodegeneration.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2605209123","type":"journal-article","created":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T18:01:52Z","timestamp":1792519312000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["CX3CL1 (fractalkine)\u2013CX3CR1 interface drives CD8\u207a T cell\u2013induced neurodegeneration in human brain organoids"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2358-8287","authenticated-orcid":false,"given":"Woo Sub","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Genetics, Interdepartmental Neuroscience Program, Yale Stem Cell Center, Yale Child Study Center, Wu Tsai Institute, Yale School of Medicine","place":["New Haven"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2516-9251","authenticated-orcid":false,"given":"Min Sun","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Section of Rheumatology, Allergy & Immunology, Yale School of Medicine","place":["New Haven"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mu Seog","family":"Choe","sequence":"additional","affiliation":[{"name":"Department of Genetics, Interdepartmental Neuroscience Program, Yale Stem Cell Center, Yale Child Study Center, Wu Tsai Institute, Yale School of Medicine","place":["New Haven"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ferdi Ridvan","family":"Kiral","sequence":"additional","affiliation":[{"name":"Department of Genetics, Interdepartmental Neuroscience Program, Yale Stem Cell Center, Yale Child Study Center, Wu Tsai Institute, Yale School of Medicine","place":["New Haven"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jumee","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Genetics, Interdepartmental Neuroscience Program, Yale Stem Cell Center, Yale Child Study Center, Wu Tsai Institute, Yale School of Medicine","place":["New Haven"]},{"id":[{"id":"https:\/\/ror.org\/00vvvt117","id-type":"ROR","asserted-by":"publisher"}],"name":"College of Pharmacy, Sookmyung Women\u2019s University","place":["Seoul, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0659-5896","authenticated-orcid":false,"given":"Hong-Jai","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Section of Rheumatology, Allergy & Immunology, Yale School of Medicine","place":["New 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S. Yang CX3CL1 (fractalkine)\u2013CX3CR1 interface drives CD8\u207a T cell\u2013induced neurodegeneration in human brain organoids. NCBI Gene Expression Omnibus (GEO). https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE318014. Deposited 29 January 2026."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2605209123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T18:02:51Z","timestamp":1792519371000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2605209123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,20]]},"references-count":38,"journal-issue":{"issue":"43","published-print":{"date-parts":[[2026,10,27]]}},"alternative-id":["10.1073\/pnas.2605209123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2605209123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,20]]},"assertion":[{"value":"2026-02-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-24","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-20","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2605209123"}}