{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T23:46:51Z","timestamp":1792453611024,"version":"4.5.0"},"reference-count":59,"publisher":"Rockefeller University Press","issue":"5","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2005,3,7]]},"abstract":"<jats:p>Interleukin (IL)-2 plays a crucial role in the maintenance of natural immunologic self-tolerance. Neutralization of circulating IL-2 by anti\u2013IL-2 monoclonal antibody for a limited period elicits autoimmune gastritis in BALB\/c mice. Similar treatment of diabetes-prone nonobese diabetic mice triggers early onset of diabetes and produces a wide spectrum of T cell\u2013mediated autoimmune diseases, including gastritis, thyroiditis, sialadenitis, and notably, severe neuropathy. Such treatment selectively reduces the number of Foxp3-expressing CD25+ CD4+ T cells, but not CD25\u2212 CD4+ T cells, in the thymus and periphery of normal and thymectomized mice. IL-2 neutralization inhibits physiological proliferation of peripheral CD25+ CD4+ T cells that are presumably responding to normal self-antigens, whereas it is unable to inhibit their lymphopenia-induced homeostatic expansion in a T cell\u2013deficient environment. In normal naive mice, CD25low CD4+ nonregulatory T cells actively transcribe the IL-2 gene and secrete IL-2 protein in the physiological state. IL-2 is thus indispensable for the peripheral maintenance of natural CD25+ CD4+ regulatory T cells (T reg cells). The principal physiological source of IL-2 for the maintenance of T reg cells appears to be other T cells, especially CD25low CD4+ activated T cells, which include self-reactive T cells. Furthermore, impairment of this negative feedback loop via IL-2 can be a cause and a predisposing factor for autoimmune disease.<\/jats:p>","DOI":"10.1084\/jem.20041982","type":"journal-article","created":{"date-parts":[[2005,3,7]],"date-time":"2005-03-07T14:38:03Z","timestamp":1110206283000},"page":"723-735","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":1057,"title":["Homeostatic maintenance of natural\n                    <i>Foxp3<\/i>\n                    + CD25+ CD4+ regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization"],"prefix":"10.1084","volume":"201","author":[{"given":"Ruka","family":"Setoguchi","sequence":"first","affiliation":[{"name":"1Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shohei","family":"Hori","sequence":"additional","affiliation":[{"name":"2Research Center for Allergy and Immunology, Institute for Physical and Chemical Research (RIKEN), Yokohama 230-0045, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Takahashi","sequence":"additional","affiliation":[{"name":"1Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shimon","family":"Sakaguchi","sequence":"additional","affiliation":[{"name":"1Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan"},{"name":"2Research Center for Allergy and Immunology, Institute for Physical and Chemical Research (RIKEN), Yokohama 230-0045, Japan"},{"name":"3Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Kawaguchi 332-0012, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2005,3,7]]},"reference":[{"key":"2023072512535675100_BIB1","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1111\/j.1600-065X.1995.tb00092.x","volume":"148","year":"1995","journal-title":"Immunol. 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