{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T07:01:13Z","timestamp":1790146873377,"version":"4.0.1"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Thymocytes upregulate expression of recombination activating genes (RAGs) upon developmental transition from the CD4\n                    <jats:sup>\u2212<\/jats:sup>\n                    CD8\n                    <jats:sup>\u2212<\/jats:sup>\n                    double-negative to the CD4\n                    <jats:sup>+<\/jats:sup>\n                    CD8\n                    <jats:sup>+<\/jats:sup>\n                    double-positive (DP) stage. Although enhanced RAG expression is necessary to generate a complete\n                    <jats:italic>Tcra<\/jats:italic>\n                    repertoire, here we demonstrate that elevated RAG expression simultaneously compromises DP thymocyte survival\n                    <jats:italic>in vitro<\/jats:italic>\n                    . Using a series of mouse models in which the expression and activity of RAG proteins varied, we attribute this apparent toxicity to elevated expression of RAG1 protein, independent of its association with RAG2 and its canonical role as a nuclease for V(D)J recombination. We propose that this toxicity accounts for the previously documented expansion of the DP compartment in mice with reduced RAG expression\n                    <jats:italic>in vivo<\/jats:italic>\n                    . These results indicate that DP thymocytes endure RAG1-compromised survival as a necessary trade-off for the formation of a complete\n                    <jats:italic>Tcra<\/jats:italic>\n                    repertoire and suggest novel aspects of RAG1 biology unrelated to V(D)J recombination.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1849780","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T06:16:10Z","timestamp":1790144170000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Physiological upregulation of RAG1 expression compromises the survival of CD4+CD8+ thymocytes in vitro"],"prefix":"10.3389","volume":"17","author":[{"given":"Abani Kanta","family":"Naik","sequence":"first","affiliation":[{"name":"Department of Integrative Immunobiology, Duke University School of Medicine","place":["Durham, NC, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javid P.","family":"Mohammed","sequence":"additional","affiliation":[{"name":"Department of Integrative Immunobiology, Duke University School of Medicine","place":["Durham, NC, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca A.","family":"Glynn","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Children\u2019s Hospital of Pennsylvania, Perelman School of Medicine, University of Pennsylvania","place":["Philadelphia, PA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig H.","family":"Bassing","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Children\u2019s Hospital of Pennsylvania, Perelman School of Medicine, University of Pennsylvania","place":["Philadelphia, PA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael S.","family":"Krangel","sequence":"additional","affiliation":[{"name":"Department of Integrative Immunobiology, Duke University School of Medicine","place":["Durham, NC, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1146\/annurev-genet-110410-132552","article-title":"V(D)J recombination: mechanisms of initiation","volume":"45","author":"Schatz","year":"2011","journal-title":"Annu Rev Genet"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.03.010","article-title":"The in vivo pattern of binding of RAG1 and RAG2 to antigen receptor loci","volume":"141","author":"Ji","year":"2010","journal-title":"Cell"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.07.009","article-title":"RAG represents a 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