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Because Tregs in Socs1fl\/flLck-Cre+ mice are constantly exposed to a large amount of inflammatory cytokines produced by non-Tregs in vivo, in this study we analyzed Treg-specific Socs1-deficient mice (Socs1fl\/flFoxp3YFP-Cre mice). These mice developed dermatitis, splenomegaly, and lymphadenopathy that were much milder than those in Socs1fl\/flLck-Cre+ mice. A fate mapping study revealed that Socs1 deficiency accelerated the conversion of Tregs to Foxp3\u2212IFN-\u03b3+ ex-Tregs in the tumor microenvironment and suppressed tumor growth. When transferred into Rag2\u2212\/\u2212 mice, Tregs from Socs1fl\/flLck-Cre+ mice easily lost Foxp3 expression, whereas those from Socs1fl\/flFoxp3YFP-Cre mice maintained Foxp3 expression. Although Tregs from Socs1fl\/flLck-Cre+ mice produced IFN-\u03b3 after a 3-d culture in response to anti-CD3\/CD28 Ab stimulation in vitro, Tregs from Socs1fl\/flFoxp3YFP-Cre mice did not. This finding suggested that the inflammatory conditions in Socs1fl\/flLck-Cre+ mice modified the born nature of Socs1-deficient Tregs. To investigate this mechanism, Tregs from Socs1fl\/flFoxp3YFP-Cre mice were cultured with APCs from Socs1fl\/flLck-Cre+ mice. These APCs facilitated STAT4 phosphorylation, IFN-\u03b3 production, and loss of Foxp3 expression in Tregs from Socs1fl\/flFoxp3YFP-Cre mice in an IL-12\u2013dependent manner. The results indicate that Socs1-deficient Tregs tend to convert into ex-Tregs under the inflammatory conditions in which APCs are highly activated, and that SOCS1 could be a useful target for enhancement of anti-tumor immunity.<\/jats:p>","DOI":"10.4049\/jimmunol.1600441","type":"journal-article","created":{"date-parts":[[2017,5,27]],"date-time":"2017-05-27T00:50:25Z","timestamp":1495846225000},"page":"149-158","source":"Crossref","is-referenced-by-count":37,"title":["SOCS1 Is a Key Molecule That Prevents Regulatory T Cell Plasticity under Inflammatory Conditions"],"prefix":"10.1093","volume":"199","author":[{"given":"Reiko","family":"Takahashi","sequence":"first","affiliation":[{"name":"Department of Immunology, Research Institute, Nozaki Tokushukai , Daitou, Osaka 574-0074,","place":["Japan"]},{"name":"Rheumatic Disease Unit, Department of Medicine, Kyushu University Beppu Hospital , Beppu 874-0838,","place":["Japan"]},{"name":"Department of Microbiology and Immunology, Keio University School of Medicine , Shinjuku-Ku, Tokyo 160-8582,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroko","family":"Nakatsukasa","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Keio University School of Medicine , Shinjuku-Ku, Tokyo 160-8582,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunichi","family":"Shiozawa","sequence":"additional","affiliation":[{"name":"Rheumatic Disease Unit, Department of Medicine, Kyushu University Beppu Hospital , Beppu 874-0838,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiko","family":"Yoshimura","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Keio University School of Medicine , Shinjuku-Ku, Tokyo 160-8582,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2017,7,1]]},"reference":[{"key":"2025030612084168500_r1","doi-asserted-by":"crossref","first-page":"1903","DOI":"10.1073\/pnas.0811556106","article-title":"Heterogeneity of natural Foxp3+ T cells: a committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity","volume":"106","author":"Komatsu","year":"2009","journal-title":"Proc. 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