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This perspective is based on the key evidence that CD25<jats:sup>+<\/jats:sup> Tregs emigrate to neonatal spleen a few days later than other T cells and that thymectomy of 3\u2010day\u2010old mice depletes Tregs only, causing autoimmune diseases. Although widely believed, the evidence has never been reproduced as originally reported, and some studies indicate that Tregs exist in neonates. Thus we examine the consequences of the controversial evidence, revisit the fundamental issues of Tregs and thereby reveal the overlooked relationship of T\u2010cell activation and Foxp3\u2010mediated control of the T\u2010cell system. Here we provide a new model of Tregs and Foxp3, a feedback control perspective, which views Tregs as a component of the system that controls T\u2010cell activation, rather than as a distinct genetically programmed lineage. This perspective provides new insights into the roles of self\u2010reactivity, T cell\u2013antigen\u2010presenting cell interaction and T\u2010cell activation in Foxp3\u2010mediated immune regulation.<\/jats:p>","DOI":"10.1038\/icb.2015.65","type":"journal-article","created":{"date-parts":[[2015,7,28]],"date-time":"2015-07-28T09:40:59Z","timestamp":1438076459000},"page":"3-10","source":"Crossref","is-referenced-by-count":27,"title":["Controversies concerning thymus\u2010derived regulatory T cells: fundamental issues and a new perspective"],"prefix":"10.1111","volume":"94","author":[{"given":"Masahiro","family":"Ono","sequence":"first","affiliation":[{"name":"Department of Life Sciences, Faculty of Natural Sciences, Imperial College London  London UK"},{"name":"Immunobiology Section, Institute of Child Health, University College London  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reiko 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