{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T07:05:48Z","timestamp":1784099148506,"version":"3.55.0"},"reference-count":80,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T00:00:00Z","timestamp":1784073600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100013061","name":"Jilin Provincial Scientific and Technological Development Program","doi-asserted-by":"publisher","award":["20220505028ZP, 20230505034ZP, 20250206028ZP, 20250206020ZP"],"award-info":[{"award-number":["20220505028ZP, 20230505034ZP, 20250206028ZP, 20250206020ZP"]}],"id":[{"id":"10.13039\/501100013061","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Early-life environmental stressors can program immune development, but how the frequency of cold stress shapes thymic programming remains unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Developmentally matched (day 4, poikilothermic, yolk sac or milk dependent) zebrafish larvae and neonatal mice were exposed to two or four cycles of cold stress (termed 2\u00d7 or 4\u00d7 stress). Thymic development (zebrafish) and thymic T cell subsets (mice) were assessed, followed by influenza A virus (IAV) challenge in mice. Mechanisms were explored by RT-qPCR, western\/dot blotting, and\n                      <jats:italic>irf4\/5<\/jats:italic>\n                      transgenic or\n                      <jats:italic>irf5<\/jats:italic>\n                      knockout zebrafish.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In\n                      <jats:italic>Tg(rag2:DsRed)<\/jats:italic>\n                      zebrafish larvae, 2\u00d7 stress increased the percentage of larvae exhibiting a DsRed\n                      <jats:sup>+<\/jats:sup>\n                      thymus, without significantly altering overall fluorescence area and MFI of the thymus, whereas 4\u00d7 stress markedly reduced both of the latter parameters. These opposite phenotypic effects correlated with divergent expression patterns of\n                      <jats:italic>lepb<\/jats:italic>\n                      ,\n                      <jats:italic>lepr<\/jats:italic>\n                      ,\n                      <jats:italic>irf4\/5<\/jats:italic>\n                      , and\n                      <jats:italic>stat3<\/jats:italic>\n                      . In neonatal mice, 2\u00d7 stress enhanced thymic CD3 expression on CD4\n                      <jats:sup>+<\/jats:sup>\n                      CD8\n                      <jats:sup>+<\/jats:sup>\n                      (DP) and CD4\n                      <jats:sup>+<\/jats:sup>\n                      cells and improved acute survival following IAV infection, whereas 4\u00d7 stress reduced DP proportion and CD3 expression across multiple subsets, increased CD4\n                      <jats:sup>+<\/jats:sup>\n                      cells, and offered no acute protection against IAV infection, yet unexpectedly enhanced long-term survival when infected as adults. 2\u00d7 and 4\u00d7 stress induced divergent dynamics of leptin, IRF4\/5 and inflammatory factors. Transgenic overexpression of\n                      <jats:italic>irf5<\/jats:italic>\n                      , but not\n                      <jats:italic>irf4<\/jats:italic>\n                      , reprogrammed the frequency-selective cold stress response in larvae,\n                      <jats:italic>irf5<\/jats:italic>\n                      knockout subsequently abrogated these effects on thymic development and altered baseline expression of leptin signaling-related genes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Early-life cold stress programs thymic immunity in a frequency-selective manner. Zebrafish genetics establish a causal requirement for IRF5, while mouse data show correlative changes in leptin signaling and IRF4\/5. These findings highlight stress frequency as a key determinant of early-life immune programming and suggest potential windows for precise immunomodulation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1851219","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T06:11:29Z","timestamp":1784095889000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Frequency-selective thymic programming by early-life cold stress requires interferon regulatory factor 5"],"prefix":"10.3389","volume":"17","author":[{"given":"Shengnan","family":"Wang","sequence":"first","affiliation":[{"name":"Medical Basic Research Innovation Center of Airway Disease in North China and Department of Molecular Biology, College of Basic Medical Sciences, Jilin University","place":["Changchun, Jilin, 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