{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T00:59:57Z","timestamp":1791507597252,"version":"4.3.4"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2011,2,1]],"date-time":"2011-02-01T00:00:00Z","timestamp":1296518400000},"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":[[2011,2,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>E3 ubiquitin ligases have been placed among the essential molecules involved in the regulation of T cell functions and T cell tolerance. However, it has never been experimentally proven in vivo whether these functions indeed depend on the catalytic E3 ligase activity. The Casitas B-cell lymphoma (Cbl) family protein Cbl-b was the first E3 ubiquitin ligase directly implicated in the activation and tolerance of the peripheral T cell. In this study, we report that selective genetic inactivation of Cbl-b E3 ligase activity phenocopies the T cell responses observed when total Cbl-b is ablated, resulting in T cell hyperactivation, spontaneous autoimmunity, and impaired induction of T cell anergy in vivo. Moreover, mice carrying a Cbl-b E3 ligase-defective mutation spontaneously reject tumor cells that express human papilloma virus Ags. These data demonstrate for the first time, to our knowledge, that the catalytic function of an E3 ligase, Cbl-b, is essential for negative regulation of T cells in vivo. Thus, modulation of the E3 ligase activity of Cbl-b might be a novel modality to control T cell immunity in vaccination, cancer biology, or autoimmunity.<\/jats:p>","DOI":"10.4049\/jimmunol.1003390","type":"journal-article","created":{"date-parts":[[2011,1,20]],"date-time":"2011-01-20T04:02:34Z","timestamp":1295496154000},"page":"2138-2147","source":"Crossref","is-referenced-by-count":89,"title":["Essential Role of E3 Ubiquitin Ligase Activity in <i>Cbl-b\u2013<\/i>Regulated T Cell Functions"],"prefix":"10.1093","volume":"186","author":[{"given":"Magdalena","family":"Paolino","sequence":"first","affiliation":[{"name":"Institute of Molecular Biotechnology of the Austrian Academy of Science , A-1030 Vienna ,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine B F","family":"Thien","sequence":"additional","affiliation":[{"name":"School of Pathology and Laboratory Medicine, University of Western Australia, Crawley , Perth, Western Australia 6009 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Gruber","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Clinical and Molecular Pharmacology, Medical University of Innsbruck , A-6020 Innsbruck ,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reinhard","family":"Hinterleitner","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Clinical and Molecular Pharmacology, Medical University of Innsbruck , A-6020 Innsbruck ,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gottfried","family":"Baier","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Clinical and Molecular Pharmacology, Medical University of Innsbruck , A-6020 Innsbruck ,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wallace Y","family":"Langdon","sequence":"additional","affiliation":[{"name":"School of Pathology and Laboratory Medicine, University of Western Australia, Crawley , Perth, Western Australia 6009 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josef M","family":"Penninger","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biotechnology of the Austrian Academy of Science , A-1030 Vienna ,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2011,2,15]]},"reference":[{"key":"2025032411071450800_r1","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1038\/nature07959","article-title":"Ubiquitylation in innate and adaptive immunity","volume":"458","author":"Bhoj","year":"2009","journal-title":"Nature"},{"key":"2025032411071450800_r2","doi-asserted-by":"crossref","first-page":"2337","DOI":"10.1002\/eji.200939662","article-title":"E3 ubiquitin ligases in T-cell tolerance","volume":"39","author":"Paolino","year":"2009","journal-title":"Eur. J. Immunol."},{"key":"2025032411071450800_r3","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1038\/nri1731","article-title":"Immunity by ubiquitylation: a reversible process of modification","volume":"5","author":"Liu","year":"2005","journal-title":"Nat. Rev. Immunol."},{"key":"2025032411071450800_r4","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1146\/annurev.biochem.70.1.503","article-title":"Mechanisms underlying ubiquitination","volume":"70","author":"Pickart","year":"2001","journal-title":"Annu. Rev. Biochem."},{"key":"2025032411071450800_r5","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1038\/nrm1700","article-title":"Ubiquitin and ubiquitin-like proteins as multifunctional signals","volume":"6","author":"Welchman","year":"2005","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2025032411071450800_r6","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1038\/35003228","article-title":"Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b","volume":"403","author":"Bachmaier","year":"2000","journal-title":"Nature"},{"key":"2025032411071450800_r7","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1038\/35003235","article-title":"Cbl-b regulates the CD28 dependence of T-cell activation","volume":"403","author":"Chiang","year":"2000","journal-title":"Nature"},{"key":"2025032411071450800_r8","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/S0378-1119(03)00471-2","article-title":"Comparative genomic organization of the cbl genes","volume":"308","author":"Nau","year":"2003","journal-title":"Gene"},{"key":"2025032411071450800_r9","doi-asserted-by":"crossref","first-page":"6382","DOI":"10.1038\/sj.onc.1204781","article-title":"Beyond the RING: CBL proteins as multivalent adapters","volume":"20","author":"Tsygankov","year":"2001","journal-title":"Oncogene"},{"key":"2025032411071450800_r10","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1038\/nrm1762","article-title":"The Cbl interactome and its functions","volume":"6","author":"Schmidt","year":"2005","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2025032411071450800_r11","doi-asserted-by":"crossref","first-page":"22151","DOI":"10.1074\/jbc.274.32.22151","article-title":"The RING finger of c-Cbl mediates desensitization of the epidermal growth factor receptor","volume":"274","author":"Waterman","year":"1999","journal-title":"J. Biol. Chem."},{"key":"2025032411071450800_r12","doi-asserted-by":"crossref","first-page":"27677","DOI":"10.1074\/jbc.M102641200","article-title":"Cbl-b-dependent coordinated degradation of the epidermal growth factor receptor signaling complex","volume":"276","author":"Ettenberg","year":"2001","journal-title":"J. Biol. Chem."},{"key":"2025032411071450800_r13","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1126\/science.286.5438.309","article-title":"The tyrosine kinase negative regulator c-Cbl as a RING-type, E2-dependent ubiquitin-protein ligase","volume":"286","author":"Joazeiro","year":"1999","journal-title":"Science"},{"key":"2025032411071450800_r14","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/S0092-8674(00)00057-X","article-title":"Structure of a c-Cbl-UbcH7 complex: RING domain function in ubiquitin-protein ligases","volume":"102","author":"Zheng","year":"2000","journal-title":"Cell"},{"key":"2025032411071450800_r15","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.immuni.2004.07.013","article-title":"Essential role of the E3 ubiquitin ligase Cbl-b in T cell anergy induction","volume":"21","author":"Jeon","year":"2004","journal-title":"Immunity"},{"key":"2025032411071450800_r16","doi-asserted-by":"crossref","first-page":"1234","DOI":"10.1038\/nm1114","article-title":"TCR affinity and negative regulation limit autoimmunity","volume":"10","author":"Gronski","year":"2004","journal-title":"Nat. Med."},{"key":"2025032411071450800_r17","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1172\/JCI29472","article-title":"Ablation of Cbl-b provides protection against transplanted and spontaneous tumors","volume":"117","author":"Chiang","year":"2007","journal-title":"J. Clin. Invest."},{"key":"2025032411071450800_r18","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1084\/jem.20061699","article-title":"Spontaneous tumor rejection by cbl-b-deficient CD8+ T cells","volume":"204","author":"Loeser","year":"2007","journal-title":"J. Exp. Med."},{"key":"2025032411071450800_r19","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1038\/ni763","article-title":"Dysregulation of T lymphocyte function in itchy mice: a role for Itch in TH2 differentiation","volume":"3","author":"Fang","year":"2002","journal-title":"Nat. Immunol."},{"key":"2025032411071450800_r20","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1016\/j.immuni.2010.05.002","article-title":"The E3 ubiquitin ligase GRAIL regulates T cell tolerance and regulatory T cell function by mediating T cell receptor-CD3 degradation","volume":"32","author":"Nurieva","year":"2010","journal-title":"Immunity"},{"key":"2025032411071450800_r21","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1038\/ni1047","article-title":"Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins","volume":"5","author":"Heissmeyer","year":"2004","journal-title":"Nat. Immunol."},{"key":"2025032411071450800_r22","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/S1074-7613(03)00084-0","article-title":"GRAIL: an E3 ubiquitin ligase that inhibits cytokine gene transcription is expressed in anergic CD4+ T cells","volume":"18","author":"Anandasabapathy","year":"2003","journal-title":"Immunity"},{"key":"2025032411071450800_r23","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1172\/JCI26858","article-title":"Convergence of Itch-induced ubiquitination with MEKK1-JNK signaling in Th2 tolerance and airway inflammation","volume":"116","author":"Venuprasad","year":"2006","journal-title":"J. Clin. Invest."},{"key":"2025032411071450800_r24","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.immuni.2010.07.002","article-title":"K33-linked polyubiquitination of T cell receptor-zeta regulates proteolysis-independent T cell signaling","volume":"33","author":"Huang","year":"2010","journal-title":"Immunity"},{"key":"2025032411071450800_r25","doi-asserted-by":"crossref","first-page":"4872","DOI":"10.1074\/jbc.M008901200","article-title":"Cbl-b, a RING-type E3 ubiquitin ligase, targets phosphatidylinositol 3-kinase for ubiquitination in T cells","volume":"276","author":"Fang","year":"2001","journal-title":"J. Biol. Chem."},{"key":"2025032411071450800_r26","doi-asserted-by":"crossref","first-page":"23978","DOI":"10.1074\/jbc.M212671200","article-title":"Negative regulation of T cell antigen receptor-mediated Crk-L-C3G signaling and cell adhesion by Cbl-b","volume":"278","author":"Zhang","year":"2003","journal-title":"J. Biol. Chem."},{"key":"2025032411071450800_r27","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/ni1564","article-title":"The E3 ubiquitin ligase Itch regulates expression of transcription factor Foxp3 and airway inflammation by enhancing the function of transcription factor TIEG1","volume":"9","author":"Venuprasad","year":"2008","journal-title":"Nat. Immunol."},{"key":"2025032411071450800_r28","doi-asserted-by":"crossref","first-page":"7559","DOI":"10.4049\/jimmunol.177.11.7559","article-title":"A novel E3 ubiquitin ligase substrate screen identifies Rho guanine dissociation inhibitor as a substrate of gene related to anergy in lymphocytes","volume":"177","author":"Su","year":"2006","journal-title":"J. Immunol."},{"key":"2025032411071450800_r29","doi-asserted-by":"crossref","first-page":"1622","DOI":"10.4049\/jimmunol.181.3.1622","article-title":"Cutting edge: the transmembrane E3 ligase GRAIL ubiquitinates the costimulatory molecule CD40 ligand during the induction of T cell anergy","volume":"181","author":"Lineberry","year":"2008","journal-title":"J. Immunol."},{"key":"2025032411071450800_r30","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1016\/j.molimm.2007.08.002","article-title":"The Cbl-b RING finger domain has a limited role in regulating inflammatory cytokine production by IgE-activated mast cells","volume":"45","author":"Oksvold","year":"2008","journal-title":"Mol. Immunol."},{"key":"2025032411071450800_r31","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1126\/science.1075958","article-title":"Projection of an immunological self shadow within the thymus by the aire protein","volume":"298","author":"Anderson","year":"2002","journal-title":"Science"},{"key":"2025032411071450800_r32","first-page":"21","article-title":"Treatment of established tumors with a novel vaccine that enhances major histocompatibility class II presentation of tumor antigen","volume":"56","author":"Lin","year":"1996","journal-title":"Cancer Res."},{"key":"2025032411071450800_r33","doi-asserted-by":"crossref","first-page":"3807","DOI":"10.1038\/sj.emboj.7600841","article-title":"Loss of c-Cbl RING finger function results in high-intensity TCR signaling and thymic deletion","volume":"24","author":"Thien","year":"2005","journal-title":"EMBO J."},{"key":"2025032411071450800_r34","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1038\/342559a0","article-title":"Tolerance induction in double specific T-cell receptor transgenic mice varies with antigen","volume":"342","author":"Pircher","year":"1989","journal-title":"Nature"},{"key":"2025032411071450800_r35","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1038\/10495","article-title":"CD40 activation in vivo overcomes peptide-induced peripheral cytotoxic T-lymphocyte tolerance and augments anti-tumor vaccine efficacy","volume":"5","author":"Diehl","year":"1999","journal-title":"Nat. Med."},{"key":"2025032411071450800_r36","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1038\/35067100","article-title":"Cbl: many adaptations to regulate protein tyrosine kinases","volume":"2","author":"Thien","year":"2001","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2025032411071450800_r37","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1016\/j.immuni.2007.03.015","article-title":"Control of the B cell-intrinsic tolerance programs by ubiquitin ligases Cbl and Cbl-b","volume":"26","author":"Kitaura","year":"2007","journal-title":"Immunity"},{"key":"2025032411071450800_r38","doi-asserted-by":"crossref","first-page":"4473","DOI":"10.4049\/jimmunol.179.7.4473","article-title":"Negative regulation of CD40-mediated B cell responses by E3 ubiquitin ligase Casitas-B-lineage lymphoma protein-B","volume":"179","author":"Qiao","year":"2007","journal-title":"J. Immunol."},{"key":"2025032411071450800_r39","doi-asserted-by":"crossref","first-page":"1779","DOI":"10.1182\/blood-2003-07-2260","article-title":"Negative regulation of FcepsilonRI-mediated mast cell activation by a ubiquitin-protein ligase Cbl-b","volume":"103","author":"Qu","year":"2004","journal-title":"Blood"},{"key":"2025032411071450800_r40","doi-asserted-by":"crossref","first-page":"2511","DOI":"10.2337\/db06-1768","article-title":"Deficiency of Cbl-b gene enhances infiltration and activation of macrophages in adipose tissue and causes peripheral insulin resistance in mice","volume":"56","author":"Hirasaka","year":"2007","journal-title":"Diabetes"},{"key":"2025032411071450800_r41","doi-asserted-by":"crossref","first-page":"17847","DOI":"10.1073\/pnas.0904078106","article-title":"Mechanisms of NKT cell anergy induction involve Cbl-b-promoted monoubiquitination of CARMA1","volume":"106","author":"Kojo","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032411071450800_r42","doi-asserted-by":"crossref","first-page":"1381","DOI":"10.1084\/jem.20100004","article-title":"Transcription factors Foxo3a and Foxo1 couple the E3 ligase Cbl-b to the induction of Foxp3 expression in induced regulatory T cells","volume":"207","author":"Harada","year":"2010","journal-title":"J. Exp. Med."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/186\/4\/2138\/62470775\/1003390.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/186\/4\/2138\/62470775\/1003390.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T10:06:47Z","timestamp":1743156407000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/186\/4\/2138\/7990201"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,2]]},"references-count":42,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2011,2,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1003390","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2011,2]]},"published":{"date-parts":[[2011,2]]}}}