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Resistance of TSC1-deficient T cells to anergy is correlated with increased signaling through the mammalian target of rapamycin complex (mTORC)1 and can be reverted by treatment of these cells with mTORC1 inhibitor rapamycin. Expression of the inducible costimulator (ICOS) is increased in TSC1-deficient T cells, which can be inhibited by rapamycin. Simultaneous blockade of both CD28 and ICOS costimulation partially restored sensitivity of TSC1-deficient T cells to anergy induction. Together, our data indicate that TSC1 is crucial for T-cell anergy by inhibiting mTORC1 signaling through both ICOS-dependent and -independent mechanisms.<\/jats:p>","DOI":"10.1073\/pnas.1119744109","type":"journal-article","created":{"date-parts":[[2012,8,13]],"date-time":"2012-08-13T22:37:49Z","timestamp":1344897469000},"page":"14152-14157","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":57,"title":["Tumor suppressor TSC1 is critical for T-cell anergy"],"prefix":"10.1073","volume":"109","author":[{"given":"Dan-Li","family":"Xie","sequence":"first","affiliation":[{"name":"Departments of aPediatrics and"},{"name":"Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine, Wenzhou Medical College, Wenzhou, Zhejiang 325035, China; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinhong","family":"Wu","sequence":"additional","affiliation":[{"name":"Departments of aPediatrics and"},{"name":"Department of Pediatrics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong-Liang","family":"Lou","sequence":"additional","affiliation":[{"name":"Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine, Wenzhou Medical College, Wenzhou, Zhejiang 325035, China; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Ping","family":"Zhong","sequence":"additional","affiliation":[{"name":"Departments of aPediatrics and"},{"name":"Immunology, Duke University Medical Center, Durham, NC 27710;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2012,8,13]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.84.15.5409"},{"key":"e_1_3_3_2_2","doi-asserted-by":"crossref","first-page":"3704","DOI":"10.4049\/jimmunol.138.11.3704","article-title":"Stimulation of normal inducer T cell clones with antigen presented by purified Ia molecules in planar lipid membranes: Specific induction of a long-lived state of proliferative nonresponsiveness","volume":"138","author":"Quill H","year":"1987","unstructured":"H Quill, RH Schwartz, Stimulation of normal inducer T cell clones with antigen presented by purified Ia molecules in planar lipid membranes: Specific induction of a long-lived state of proliferative nonresponsiveness. 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