{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T21:24:06Z","timestamp":1790717046463,"version":"4.1.0"},"reference-count":87,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,11,29]],"date-time":"2021-11-29T00:00:00Z","timestamp":1638144000000},"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>CD4<jats:sup>+<\/jats:sup>CD25<jats:sup>+<\/jats:sup>Foxp3<jats:sup>+<\/jats:sup>T cell population is heterogenous and contains three major sub-groups. First, thymus derived T regulatory cells (tTreg) that are na\u00efve\/resting. Second, activated\/memory Treg that are produced by activation of tTreg by antigen and cytokines. Third, effector lineage CD4<jats:sup>+<\/jats:sup>CD25<jats:sup>+<\/jats:sup>T cells generated from CD4<jats:sup>+<\/jats:sup>CD25<jats:sup>-<\/jats:sup>T cells\u2019 activation by antigen to transiently express CD25 and Foxp3. We have shown that freshly isolated CD4<jats:sup>+<\/jats:sup>CD25<jats:sup>+<\/jats:sup>T cells are activated by specific alloantigen and IL-4, not IL-2, to Ts2 cells that express the IL-5 receptor alpha. Ts2 cells are more potent than na\u00efve\/resting tTreg in suppressing specific alloimmunity. Here, we showed rIL-5 promoted further activation of Ts2 cells to Th2-like Treg, that expressed<jats:italic>foxp3, irf4, gata3<\/jats:italic>and<jats:italic>il5. In vivo<\/jats:italic>, we studied the effects of rIL-5 treatment on Lewis heart allograft survival in F344 rats. Host CD4<jats:sup>+<\/jats:sup>CD25<jats:sup>+<\/jats:sup>T cells were assessed by FACS, in mixed lymphocyte culture and by RT-PCR to examine mRNA of Ts2 or Th2-like Treg markers. rIL-5 treatment given 7 days after transplantation reduced the severity of rejection and all grafts survived \u226560d whereas sham treated rats fully rejected by day 31 (p&amp;lt;0.01). Treatment with anti-CD25 or anti-IL-4 monoclonal antibody abolished the benefits of treatment with rIL-5 and accelerated rejection. After 10d treatment with rIL-5, hosts\u2019 CD4<jats:sup>+<\/jats:sup>CD25<jats:sup>+<\/jats:sup>cells expressed more<jats:italic>Il5ra<\/jats:italic>and responded to specific donor Lewis but not self. Enriched CD4<jats:sup>+<\/jats:sup>CD25<jats:sup>+<\/jats:sup>cells from rIL-5 treated rats with allografts surviving &amp;gt;60 days proliferated to specific donor only when rIL-5 was present and did not proliferate to self or third party. These cells had more mRNA for molecules expressed by Th2-like Treg includin<jats:italic>g Irf4, gata3<\/jats:italic>and<jats:italic>Il5.<\/jats:italic>These findings were consistent with IL-5 treatment preventing rejection by activation of Ts2 cells and Th2-like Treg.<\/jats:p>","DOI":"10.3389\/fimmu.2021.714838","type":"journal-article","created":{"date-parts":[[2021,12,1]],"date-time":"2021-12-01T13:37:51Z","timestamp":1638365871000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Interleukin-5 (IL-5) Therapy Prevents Allograft Rejection by Promoting CD4+CD25+ Ts2 Regulatory Cells That Are Antigen-Specific and Express IL-5 Receptor"],"prefix":"10.3389","volume":"12","author":[{"given":"Bruce M.","family":"Hall","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachael M.","family":"Hall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giang T.","family":"Tran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine M.","family":"Robinson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul L.","family":"Wilcox","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prateek K.","family":"Rakesh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanmin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra F.","family":"Sharland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nirupama D.","family":"Verma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanne J.","family":"Hodgkinson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,11,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(11)60699-5","article-title":"Diagnosis and Prevention of Chronic Kidney Allograft Loss","volume":"378","author":"Nankivell","year":"2011","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1097\/MOT.0000000000000155","article-title":"Chronic Allograft Rejection: A Fresh Look","volume":"20","author":"Wedel","year":"2015","journal-title":"Curr Opin Organ Transpl"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1007\/s11883-006-0049-1","article-title":"Cardiac Allograft Vasculopathy: The Achilles\u2019 Heel of Long-Term Survival After Cardiac Transplantation","volume":"8","author":"Dhaliwal","year":"2006","journal-title":"Curr Atheroscler Rep"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.114.302818","article-title":"Interacting Mechanisms in the Pathogenesis of Cardiac Allograft Vasculopathy","volume":"34","author":"Pober","year":"2014","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1097\/00007890-198336060-00023","article-title":"The Cellular Basis of Allograft Rejection In\u00a0Vivo. 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