{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T23:16:36Z","timestamp":1792451796121,"version":"4.5.0"},"reference-count":80,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"769","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2024,10,16]]},"abstract":"<jats:p>\n            Regulatory T cells (T\n            <jats:sub>regs<\/jats:sub>\n            ) make major contributions to immune homeostasis. Because T\n            <jats:sub>reg<\/jats:sub>\n            dysfunction can lead to both allo- and autoimmunity, there is interest in correcting these disorders through T\n            <jats:sub>reg<\/jats:sub>\n            adoptive transfer. Two of the central challenges in clinically deploying T\n            <jats:sub>reg<\/jats:sub>\n            cellular therapies are ensuring phenotypic stability and maximizing potency. Here, we describe an approach to address both issues through the creation of OX40 ligand (OX40L)\u2013specific chimeric antigen receptor (CAR)\u2013T\n            <jats:sub>regs<\/jats:sub>\n            under the control of a synthetic forkhead box P3 (\n            <jats:italic>FOXP3<\/jats:italic>\n            ) promoter. The creation of these CAR-T\n            <jats:sub>regs<\/jats:sub>\n            enabled selective T\n            <jats:sub>reg<\/jats:sub>\n            stimulation by engagement of OX40L, a key activation antigen in alloimmunity, including both graft-versus-host disease and solid organ transplant rejection, and autoimmunity, including rheumatoid arthritis, systemic sclerosis, and systemic lupus erythematosus. We demonstrated that OX40L\u2013CAR-T\n            <jats:sub>regs<\/jats:sub>\n            were robustly activated in the presence of OX40L-expressing cells, leading to up-regulation of T\n            <jats:sub>reg<\/jats:sub>\n            suppressive proteins without induction of proinflammatory cytokine production. Compared with control T\n            <jats:sub>regs<\/jats:sub>\n            , OX40L\u2013CAR-T\n            <jats:sub>regs<\/jats:sub>\n            more potently suppressed alloreactive T cell proliferation in vitro and were directly inhibitory toward activated monocyte-derived dendritic cells (DCs). We identified trogocytosis as one of the central mechanisms by which these CAR-T\n            <jats:sub>regs<\/jats:sub>\n            effectively decrease extracellular display of OX40L, resulting in decreased DC stimulatory capacity. OX40L\u2013CAR-T\n            <jats:sub>regs<\/jats:sub>\n            demonstrated an enhanced ability to control xenogeneic graft-versus-host disease compared with control T\n            <jats:sub>regs<\/jats:sub>\n            without abolishing the graft-versus-leukemia effect. These results suggest that OX40L\u2013CAR-T\n            <jats:sub>regs<\/jats:sub>\n            may have wide applicability as a potent cellular therapy to control both allo- and autoimmune diseases.\n          <\/jats:p>","DOI":"10.1126\/scitranslmed.adj9331","type":"journal-article","created":{"date-parts":[[2024,10,16]],"date-time":"2024-10-16T17:58:28Z","timestamp":1729101508000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":48,"title":["Human OX40L\u2013CAR-T\n            <sub>regs<\/sub>\n            target activated antigen-presenting cells and control T cell alloreactivity"],"prefix":"10.1126","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-1219-4382","authenticated-orcid":true,"given":"Xianliang","family":"Rui","sequence":"first","affiliation":[{"name":"Division of Hematology\/Oncology, Boston Children\u2019s Hospital, Boston, MA 02115, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5620-8431","authenticated-orcid":true,"given":"Francesca","family":"Alvarez Calderon","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Boston Children\u2019s Hospital, Boston, MA 02115, USA."},{"name":"Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA."},{"name":"Harvard Medical School, Boston, MA 02115, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8978-3184","authenticated-orcid":true,"given":"Holly","family":"Wobma","sequence":"additional","affiliation":[{"name":"Harvard Medical School, Boston, MA 02115, USA."},{"name":"Division of Immunology, Boston Children\u2019s Hospital, Boston, MA 02215, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3600-0366","authenticated-orcid":true,"given":"Ulrike","family":"Gerdemann","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Boston Children\u2019s Hospital, Boston, MA 02115, USA."},{"name":"Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA."},{"name":"Harvard Medical School, Boston, MA 02115, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7093-574X","authenticated-orcid":true,"given":"Alexandre","family":"Albanese","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Boston Children\u2019s Hospital, Boston, MA 02115, USA."},{"name":"Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA."},{"name":"Harvard Medical School, Boston, MA 02115, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Cagnin","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Boston Children\u2019s Hospital, Boston, MA 02115, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8860-9926","authenticated-orcid":true,"given":"Connor","family":"McGuckin","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Boston Children\u2019s Hospital, Boston, MA 02115, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine A.","family":"Michaelis","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Boston Children\u2019s Hospital, Boston, MA 02115, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8161-3885","authenticated-orcid":true,"given":"Kisa","family":"Naqvi","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Boston Children\u2019s Hospital, Boston, MA 02115, USA."},{"name":"University of British Columbia, Vancouver, BC V6T 1Z1, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9608-9841","authenticated-orcid":true,"given":"Bruce R.","family":"Blazar","sequence":"additional","affiliation":[{"name":"Division of Pediatric Blood and Marrow Transplant and Cellular Therapy, University of Minnesota, Minneapolis, MN 55455, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6011-0576","authenticated-orcid":true,"given":"Victor","family":"Tkachev","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Boston Children\u2019s Hospital, Boston, MA 02115, USA."},{"name":"Harvard Medical School, Boston, MA 02115, USA."},{"name":"Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA 02129, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0475-3926","authenticated-orcid":true,"given":"Leslie S.","family":"Kean","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Boston Children\u2019s Hospital, Boston, MA 02115, USA."},{"name":"Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA."},{"name":"Harvard Medical School, Boston, MA 02115, 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