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We demonstrate that during immunity to a tumor\/self-Ag, the predominant role of Th cell-derived IL-2 was to maintain IL-2R\u03b1 (CD25) on CD4+ T regulatory cells (Treg), which resulted in their maintenance of the Treg cell lineage factor, Forkhead\/winged helix transcription factor (Foxp3), and tolerance. However, in the absence of Treg cells, Th cell-derived IL-2 maintained effector T cells and caused autoimmunity. IL-2R signaling was indispensable for Treg cell homeostasis and efficient suppressor function in vivo, but, surprisingly, was not required for their generation, because IL-2\u2212\/\u2212 and CD25\u2212\/\u2212 mice both contained Foxp3+ T cells in the periphery. IL-2R signaling was also important for CD8+ T cell immunity, because CD25\u2212\/\u2212 tumor-reactive CD8+ T cells failed to affect established tumors. Conversely, IL-2R signaling was not required for Th cell function. Lastly, administration of anti-IL-2 plus exogenous IL-15 to tumor-bearing mice enhanced the adoptive immunotherapy of cancer. Therefore, Th cell-derived IL-2 paradoxically controls both tolerance and immunity to a tumor\/self-Ag in vivo.<\/jats:p>","DOI":"10.4049\/jimmunol.176.9.5255","type":"journal-article","created":{"date-parts":[[2014,4,20]],"date-time":"2014-04-20T21:31:36Z","timestamp":1398029496000},"page":"5255-5266","source":"Crossref","is-referenced-by-count":108,"title":["Interleukin-2-Dependent Mechanisms of Tolerance and Immunity In Vivo"],"prefix":"10.1093","volume":"176","author":[{"given":"Paul A","family":"Antony","sequence":"first","affiliation":[{"name":"Surgery Branch, Center for Cancer Research, National Cancer Institute , Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chrystal M","family":"Paulos","sequence":"additional","affiliation":[{"name":"Surgery Branch, Center for Cancer Research, National Cancer Institute , Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mojgan","family":"Ahmadzadeh","sequence":"additional","affiliation":[{"name":"Surgery Branch, Center for Cancer Research, National Cancer Institute , Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akgu\u0308l","family":"Akpinarli","sequence":"additional","affiliation":[{"name":"Ghost Laboratory, Laboratory of Cellular and Molecular Immunology, National Institute of Allergy and Infectious Diseases , Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas C","family":"Palmer","sequence":"additional","affiliation":[{"name":"Surgery Branch, Center for Cancer Research, National Cancer Institute , Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noriko","family":"Sato","sequence":"additional","affiliation":[{"name":"Metabolism Branch, Center for Cancer Research, National Cancer Institute , Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Kaiser","sequence":"additional","affiliation":[{"name":"Surgery Branch, Center for Cancer Research, National Cancer Institute , Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Heinrichs","sequence":"additional","affiliation":[{"name":"Surgery Branch, Center for Cancer Research, National Cancer Institute , Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher A","family":"Klebanoff","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute Research Scholars Program, National Institutes of Health , Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutaka","family":"Tagaya","sequence":"additional","affiliation":[{"name":"Metabolism Branch, Center for Cancer Research, National Cancer Institute , Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas P","family":"Restifo","sequence":"additional","affiliation":[{"name":"Surgery Branch, Center for Cancer Research, National Cancer Institute , Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2006,5,1]]},"reference":[{"key":"2026020211400776500_R1","first-page":"1007","volume-title":"Science","year":"1976"},{"key":"2026020211400776500_R2","first-page":"1487","volume-title":"Science","year":"1984"},{"key":"2026020211400776500_R3","first-page":"621","volume-title":"Nature","year":"1991"},{"key":"2026020211400776500_R4","first-page":"1472","volume-title":"Science","year":"1995"},{"key":"2026020211400776500_R5","first-page":"521","volume-title":"Immunity","year":"1995"},{"key":"2026020211400776500_R6","first-page":"253","volume-title":"Cell","year":"1993"},{"key":"2026020211400776500_R7","first-page":"3168","volume-title":"Proc. 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