{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T03:08:34Z","timestamp":1791947314646,"version":"4.3.4"},"reference-count":48,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2010,8,1]],"date-time":"2010-08-01T00:00:00Z","timestamp":1280620800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2010,8,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Mice with a mutation of the \u03b6-associated protein of 70 kDa gene (skg mutation) are genetically prone to develop autoimmune arthritis, depending on the environment. In a set of mice with the mutation, the amount of \u03b6-associated protein of 70 kDa protein as well as its tyrosine phosphorylation upon TCR stimulation decreased from +\/+, skg\/+, skg\/skg, to skg\/\u2212 mice in a stepwise manner. The reduction resulted in graded alterations of thymic positive and negative selection of self-reactive T cells and Foxp3+ natural regulatory T cells (Tregs) and their respective functions. Consequently, skg\/\u2212 mice spontaneously developed autoimmune arthritis even in a microbially clean environment, whereas skg\/skg mice required stimulation through innate immunity for disease manifestation. After Treg depletion, organ-specific autoimmune diseases, especially autoimmune gastritis, predominantly developed in +\/+, at a lesser incidence in skg\/+, but not in skg\/skg BALB\/c mice, which suffered from other autoimmune diseases, especially autoimmune arthritis. In correlation with this change, gastritis-mediating TCR transgenic T cells were positively selected in +\/+, less in skg\/+, but not in skg\/skg BALB\/c mice. Similarly, on the genetic background of diabetes-prone NOD mice, diabetes spontaneously developed in +\/+, at a lesser incidence in skg\/+, but not in skg\/skg mice, which instead succumbed to arthritis. Thus, the graded attenuation of TCR signaling alters the repertoire and the function of autoimmune T cells and natural Tregs in a progressive manner. It also changes the dependency of disease development on environmental stimuli. These findings collectively provide a model of how genetic anomaly of T cell signaling contributes to the development of autoimmune disease.<\/jats:p>","DOI":"10.4049\/jimmunol.1000848","type":"journal-article","created":{"date-parts":[[2010,7,19]],"date-time":"2010-07-19T22:27:24Z","timestamp":1279578444000},"page":"2295-2305","source":"Crossref","is-referenced-by-count":107,"title":["Graded Attenuation of TCR Signaling Elicits Distinct Autoimmune Diseases by Altering Thymic T Cell Selection and Regulatory T Cell Function"],"prefix":"10.1093","volume":"185","author":[{"given":"Satoshi","family":"Tanaka","sequence":"first","affiliation":[{"name":"Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University , Kyoto"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinji","family":"Maeda","sequence":"additional","affiliation":[{"name":"Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University , Kyoto"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motomu","family":"Hashimoto","sequence":"additional","affiliation":[{"name":"Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University , Kyoto"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chihiro","family":"Fujimori","sequence":"additional","affiliation":[{"name":"Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University , Kyoto"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshinaga","family":"Ito","sequence":"additional","affiliation":[{"name":"Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University , Kyoto"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shin","family":"Teradaira","sequence":"additional","affiliation":[{"name":"Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University , Kyoto"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiji","family":"Hirota","sequence":"additional","affiliation":[{"name":"Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University , Kyoto"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Yoshitomi","sequence":"additional","affiliation":[{"name":"Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University , Kyoto"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoya","family":"Katakai","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Graduate School of Medicine, Kyoto University , Kyoto"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Graduate School of Medicine, Kyoto University , Kyoto"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Nomura","sequence":"additional","affiliation":[{"name":"Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University , Kyoto"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noriko","family":"Sakaguchi","sequence":"additional","affiliation":[{"name":"Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University , Kyoto"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shimon","family":"Sakaguchi","sequence":"additional","affiliation":[{"name":"Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University , Kyoto"},{"name":"Center for Genomic Medicine, Graduate School of Medicine, Kyoto University , Kyoto"},{"name":"Core Research for Evolutional Science and Technology, Japan Science and Technology Agency , Kawaguchi"},{"name":"World Premier International Immunology Frontier Research Center, Osaka University , Suita ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2010,8,15]]},"reference":[{"key":"2025032411482749800_r1","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1146\/annurev.immunol.21.120601.141107","article-title":"Positive and negative selection of T cells","volume":"21","author":"Starr","year":"2003","journal-title":"Annu. 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