{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T20:42:36Z","timestamp":1793824956943,"version":"4.6.1"},"reference-count":74,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"696","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2023,5,17]]},"abstract":"<jats:p>\n                    Autoimmune toxicity occurs in up to 60% of patients treated with immune checkpoint inhibitor (ICI) therapy for cancer and represents an increasing clinical challenge for expanding the use of these treatments. To date, human immunopathogenic studies of immune-related adverse events (IRAEs) have relied on sampling of circulating peripheral blood cells rather than affected tissues. Here, we directly obtained thyroid specimens from individuals with ICI-thyroiditis, one of the most common IRAEs, and compared immune infiltrates with those from individuals with spontaneous autoimmune Hashimoto\u2019s thyroiditis (HT) or no thyroid disease. Single-cell RNA sequencing revealed a dominant, clonally expanded population of thyroid-infiltrating cytotoxic CXCR6\n                    <jats:sup>+<\/jats:sup>\n                    CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells (effector CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells) present in ICI-thyroiditis but not HT or healthy controls. Furthermore, we identified a crucial role for interleukin-21 (IL-21), a cytokine secreted by intrathyroidal T follicular (T\n                    <jats:sub>FH<\/jats:sub>\n                    ) and T peripheral helper (T\n                    <jats:sub>PH<\/jats:sub>\n                    ) cells, as a driver of these thyrotoxic effector CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells. In the presence of IL-21, human CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells acquired the activated effector phenotype with up-regulation of the cytotoxic molecules interferon-\u03b3 (IFN-\u03b3) and granzyme B, increased expression of the chemokine receptor CXCR6, and thyrotoxic capacity. We validated these findings in vivo using a mouse model of IRAEs and further demonstrated that genetic deletion of IL-21 signaling protected ICI-treated mice from thyroid immune infiltration. Together, these studies reveal mechanisms and candidate therapeutic targets for individuals who develop IRAEs.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adg0675","type":"journal-article","created":{"date-parts":[[2023,5,17]],"date-time":"2023-05-17T13:58:16Z","timestamp":1684331896000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":59,"title":["Clonally expanded, thyrotoxic effector CD8\n                    <sup>+<\/sup>\n                    T cells driven by IL-21 contribute to checkpoint inhibitor thyroiditis"],"prefix":"10.1126","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4744-6566","authenticated-orcid":true,"given":"Melissa G.","family":"Lechner","sequence":"first","affiliation":[{"name":"Division of Endocrinology, Diabetes, and Metabolism, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8795-9588","authenticated-orcid":true,"given":"Zikang","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology, and Molecular Genetics, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4402-0025","authenticated-orcid":true,"given":"Aline T.","family":"Hoang","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology, and Molecular Genetics, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USA."},{"name":"Drexel Medical School, Philadelphia, PA 19129, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology, and Molecular Genetics, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4460-8896","authenticated-orcid":true,"given":"Jessica","family":"Ortega","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology, and Molecular Genetics, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren N.","family":"Scott","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology, and Molecular Genetics, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ho-Chung","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology, and Molecular Genetics, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9505-7998","authenticated-orcid":true,"given":"Anushi Y.","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology, and Molecular Genetics, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9773-2299","authenticated-orcid":true,"given":"Rana","family":"Yakhshi-Tafti","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology, and Molecular Genetics, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USA."},{"name":"Rosalind Franklin Medical School, Chicago, IL 60064, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3869-4939","authenticated-orcid":true,"given":"Kristy","family":"Kim","sequence":"additional","affiliation":[{"name":"UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1426-7190","authenticated-orcid":true,"given":"Willy","family":"Hugo","sequence":"additional","affiliation":[{"name":"Division of Dermatology, Department of Medicine, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3686-7186","authenticated-orcid":true,"given":"Pouyan","family":"Famini","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes, and Metabolism, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Drakaki","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3669-8458","authenticated-orcid":true,"given":"Antoni","family":"Ribas","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9929-0188","authenticated-orcid":true,"given":"Trevor E.","family":"Angell","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Diabetes, USC Keck School of Medicine, Los Angeles, CA 90033, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3680-9982","authenticated-orcid":true,"given":"Maureen A.","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology, and Molecular Genetics, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, 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Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scitranslmed.adg0675","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,16]],"date-time":"2024-01-16T13:47:34Z","timestamp":1705412854000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adg0675"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,17]]},"references-count":74,"journal-issue":{"issue":"696","published-print":{"date-parts":[[2023,5,17]]}},"alternative-id":["10.1126\/scitranslmed.adg0675"],"URL":"https:\/\/doi.org\/10.1126\/scitranslmed.adg0675","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.742649744.793599797","asserted-by":"object"}]},"ISSN":["1946-6234","1946-6242"],"issn-type":[{"value":"1946-6234","type":"print"},{"value":"1946-6242","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,17]]},"assertion":[{"value":"2022-11-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication 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