{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T14:38:12Z","timestamp":1769524692502,"version":"3.49.0"},"reference-count":42,"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>Cbl-b is an E3 ubiquitin ligase that negatively regulates T cell activation. Cbl-b\u2212\/\u2212 mice develop spontaneous autoimmunity, and Cbl-b dysregulation has been described in both murine and human autoimmune diseases. Although the mechanisms underlying the development of autoimmunity in Cbl-b\u2212\/\u2212 mice are not yet clear, we have reported that Cbl-b\u2212\/\u2212 CD4+CD25\u2212 effector T cells (Teffs) are resistant to CD4+CD25+ regulatory T cell (Treg)-mediated suppression in vitro and have suggested that this may be an important mechanism in the development of autoimmunity. To confirm the relevance of this resistance to autoimmune disease, we now show that Cbl-b\u2212\/\u2212 Teffs are resistant to suppression by Tregs in vivo and that this involves a resistance of truly naive Cbl-b\u2212\/\u2212 Teffs. Additionally, we show that Cbl-b\u2212\/\u2212 Tregs are fully functional in vivo, further suggesting that the regulatory abnormalities in Cbl-b\u2212\/\u2212 mice are related to defects in Teff, not Treg, function. To characterize the relevance of TGF-\u03b2 sensitivity in Treg resistance, we examined in vivo Th17 generation and report that Cbl-b\u2212\/\u2212 mice are able to mount a normal Th17 response in vivo. As Cbl-b\u2212\/\u2212 Teffs have been shown to be insensitive to the suppressive effects of TGF-\u03b2 in other in vivo models, the present results suggest that Cbl-b\u2212\/\u2212 Teffs demonstrate a context-dependent sensitivity to TGF-\u03b2 in vivo. Overall, our results suggest that resistance to Tregs may be a bona fide mechanism underlying autoimmunity and that Cbl-b\u2212\/\u2212 mice offer unique approaches for studying the interrelationships between Treg function, TGF-\u03b2\u2013mediated responses, and the development of autoimmunity.<\/jats:p>","DOI":"10.4049\/jimmunol.1001171","type":"journal-article","created":{"date-parts":[[2010,7,12]],"date-time":"2010-07-12T19:43:36Z","timestamp":1278963816000},"page":"2051-2058","source":"Crossref","is-referenced-by-count":34,"title":["Cbl-b\u2212\/\u2212 T Cells Demonstrate In Vivo Resistance to Regulatory T Cells but a Context-Dependent Resistance to TGF-\u03b2"],"prefix":"10.1093","volume":"185","author":[{"given":"Catherine O","family":"Adams","sequence":"first","affiliation":[{"name":"Department of Immunology, University of Connecticut Health Center , Farmington, CT 06032"},{"name":"Department of Medicine, University of Connecticut Health Center , Farmington, CT 06032"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William J","family":"Housley","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Connecticut Health Center , Farmington, CT 06032"},{"name":"Department of Medicine, University of Connecticut Health Center , Farmington, CT 06032"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sourojit","family":"Bhowmick","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Connecticut Health Center , Farmington, CT 06032"},{"name":"Department of Medicine, University of Connecticut Health Center , Farmington, CT 06032"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert E","family":"Cone","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Connecticut Health Center , Farmington, CT 06032"},{"name":"Department of Medicine, University of Connecticut Health Center , Farmington, CT 06032"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thiruchandurai V","family":"Rajan","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Connecticut Health Center , Farmington, CT 06032"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Faripour","family":"Forouhar","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Connecticut Health Center , Farmington, CT 06032"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert B","family":"Clark","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Connecticut Health Center , Farmington, CT 06032"},{"name":"Department of Medicine, University of Connecticut Health Center , Farmington, CT 06032"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2010,8,15]]},"reference":[{"key":"2025032411461351400_r1","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1038\/ni0901-870","article-title":"Proteolysis-independent regulation of PI3K by Cbl-b-mediated ubiquitination in T cells","volume":"2","author":"Fang","year":"2001","journal-title":"Nat. Immunol."},{"key":"2025032411461351400_r2","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":"2025032411461351400_r3","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":"2025032411461351400_r4","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":"2025032411461351400_r5","doi-asserted-by":"crossref","first-page":"4975","DOI":"10.4049\/jimmunol.0901243","article-title":"The E3 ubiquitin ligase Cbl-b regulates expansion but not functional activity of self-reactive CD4 T cells","volume":"183","author":"St Rose","year":"2009","journal-title":"J. Immunol."},{"key":"2025032411461351400_r6","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":"2025032411461351400_r7","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.4049\/jimmunol.173.2.1059","article-title":"Resistance to CD4+CD25+ regulatory T cells and TGF-beta in Cbl-b-\/- mice","volume":"173","author":"Wohlfert","year":"2004","journal-title":"J. Immunol."},{"key":"2025032411461351400_r8","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.4049\/jimmunol.176.3.1316","article-title":"Cutting edge: deficiency in the E3 ubiquitin ligase Cbl-b results in a multifunctional defect in T cell TGF-beta sensitivity in vitro and in vivo","volume":"176","author":"Wohlfert","year":"2006","journal-title":"J. Immunol."},{"key":"2025032411461351400_r9","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1002\/art.20976","article-title":"MRL\/Mp CD4+,CD25- T cells show reduced sensitivity to suppression by CD4+,CD25+ regulatory T cells in vitro: a novel defect of T cell regulation in systemic lupus erythematosus","volume":"52","author":"Monk","year":"2005","journal-title":"Arthritis Rheum."},{"key":"2025032411461351400_r10","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.2337\/diabetes.54.5.1415","article-title":"Autoimmune diabetes onset results from qualitative rather than quantitative age-dependent changes in pathogenic T-cells","volume":"54","author":"You","year":"2005","journal-title":"Diabetes"},{"key":"2025032411461351400_r11","doi-asserted-by":"crossref","first-page":"2120","DOI":"10.1002\/art.23556","article-title":"Reduced CD4+,CD25- T cell sensitivity to the suppressive function of CD4+,CD25high,CD127 -\/low regulatory T cells in patients with active systemic lupus erythematosus","volume":"58","author":"Venigalla","year":"2008","journal-title":"Arthritis Rheum."},{"key":"2025032411461351400_r12","doi-asserted-by":"crossref","first-page":"7350","DOI":"10.4049\/jimmunol.181.10.7350","article-title":"The effector T cells of diabetic subjects are resistant to regulation via CD4+ FOXP3+ regulatory T cells","volume":"181","author":"Schneider","year":"2008","journal-title":"J. Immunol."},{"key":"2025032411461351400_r13","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1038\/nm.1953","article-title":"Adjuvant IL-7 antagonizes multiple cellular and molecular inhibitory networks to enhance immunotherapies","volume":"15","author":"Pellegrini","year":"2009","journal-title":"Nat. Med."},{"key":"2025032411461351400_r14","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1093\/intimm\/dxp023","article-title":"T cell sensitivity to TGF-beta is required for the effector function but not the generation of splenic CD8+ regulatory T cells induced via the injection of antigen into the anterior chamber","volume":"21","author":"Cone","year":"2009","journal-title":"Int. Immunol."},{"key":"2025032411461351400_r15","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1038\/nm1564","article-title":"Myelin-specific regulatory T cells accumulate in the CNS but fail to control autoimmune inflammation","volume":"13","author":"Korn","year":"2007","journal-title":"Nat. Med."},{"key":"2025032411461351400_r16","doi-asserted-by":"crossref","first-page":"7058","DOI":"10.1073\/pnas.82.20.7058","article-title":"The murine bm12 gene conversion provides evidence that T cells recognize predominantly Ia conformation","volume":"82","author":"Tse","year":"1985","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032411461351400_r17","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1084\/jem.180.1.307","article-title":"Profound atrophy of the bone marrow reflecting major histocompatibility complex class II-restricted destruction of stem cells by CD4+ cells","volume":"180","author":"Sprent","year":"1994","journal-title":"J. Exp. Med."},{"key":"2025032411461351400_r18","doi-asserted-by":"crossref","first-page":"3493","DOI":"10.1182\/blood.V99.10.3493","article-title":"The infusion of ex vivo activated and expanded CD4(+)CD25(+) immune regulatory cells inhibits graft-versus-host disease lethality","volume":"99","author":"Taylor","year":"2002","journal-title":"Blood"},{"key":"2025032411461351400_r19","doi-asserted-by":"crossref","first-page":"19954","DOI":"10.1073\/pnas.0704397104","article-title":"Allograft rejection mediated by memory T cells is resistant to regulation","volume":"104","author":"Yang","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032411461351400_r20","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1111\/j.1365-2567.2008.02866.x","article-title":"The influence of CD4 T-cell subsets on control of CD4 T-cell-mediated graft-versus-host disease","volume":"125","author":"Moncrieffe","year":"2008","journal-title":"Immunology"},{"key":"2025032411461351400_r21","doi-asserted-by":"crossref","first-page":"3348","DOI":"10.4049\/jimmunol.171.7.3348","article-title":"Cutting edge: CD28 controls peripheral homeostasis of CD4+CD25+ regulatory T cells","volume":"171","author":"Tang","year":"2003","journal-title":"J. Immunol."},{"key":"2025032411461351400_r22","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1038\/ni.1743","article-title":"The receptor S1P1 overrides regulatory T cell-mediated immune suppression through Akt-mTOR","volume":"10","author":"Liu","year":"2009","journal-title":"Nat. Immunol."},{"key":"2025032411461351400_r23","doi-asserted-by":"crossref","first-page":"2014","DOI":"10.1182\/blood-2006-07-035279","article-title":"Altered activation of AKT is required for the suppressive function of human CD4+CD25+ T regulatory cells","volume":"109","author":"Crellin","year":"2007","journal-title":"Blood"},{"key":"2025032411461351400_r24","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1038\/nature04753","article-title":"Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells","volume":"441","author":"Bettelli","year":"2006","journal-title":"Nature"},{"key":"2025032411461351400_r25","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":"2025032411461351400_r26","doi-asserted-by":"crossref","first-page":"566","DOI":"10.4049\/jimmunol.177.1.566","article-title":"IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis","volume":"177","author":"Komiyama","year":"2006","journal-title":"J. Immunol."},{"key":"2025032411461351400_r27","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.cellimm.2005.11.002","article-title":"Therapeutic efficacy of IL-17 neutralization in murine experimental autoimmune encephalomyelitis","volume":"237","author":"Hofstetter","year":"2005","journal-title":"Cell. Immunol."},{"key":"2025032411461351400_r28","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.immuni.2006.01.001","article-title":"TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells","volume":"24","author":"Veldhoen","year":"2006","journal-title":"Immunity"},{"key":"2025032411461351400_r29","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1038\/nature04754","article-title":"Transforming growth factor-beta induces development of the T(H)17 lineage","volume":"441","author":"Mangan","year":"2006","journal-title":"Nature"},{"key":"2025032411461351400_r30","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1038\/nature06878","article-title":"TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function","volume":"453","author":"Zhou","year":"2008","journal-title":"Nature"},{"key":"2025032411461351400_r31","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/j.immuni.2007.02.009","article-title":"Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation","volume":"26","author":"Laurence","year":"2007","journal-title":"Immunity"},{"key":"2025032411461351400_r32","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1038\/ni1254","article-title":"Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages","volume":"6","author":"Harrington","year":"2005","journal-title":"Nat. Immunol."},{"key":"2025032411461351400_r33","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1038\/ni855","article-title":"c-Cbl and Cbl-b regulate T cell responsiveness by promoting ligand-induced TCR down-modulation","volume":"3","author":"Naramura","year":"2002","journal-title":"Nat. Immunol."},{"key":"2025032411461351400_r34","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1084\/jem.188.2.287","article-title":"CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production","volume":"188","author":"Thornton","year":"1998","journal-title":"J. Exp. Med."},{"key":"2025032411461351400_r35","doi-asserted-by":"crossref","first-page":"6519","DOI":"10.4049\/jimmunol.172.11.6519","article-title":"Cutting edge: IL-2 is critically required for the in vitro activation of CD4+CD25+ T cell suppressor function","volume":"172","author":"Thornton","year":"2004","journal-title":"J. Immunol."},{"key":"2025032411461351400_r36","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.it.2007.02.003","article-title":"\u2018Vive la R\u00e9sistance!\u2019\u2014the PI3K-Akt pathway can determine target sensitivity to regulatory T cell suppression","volume":"28","author":"Wohlfert","year":"2007","journal-title":"Trends Immunol."},{"key":"2025032411461351400_r37","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":"2025032411461351400_r38","doi-asserted-by":"crossref","first-page":"3746","DOI":"10.4049\/jimmunol.180.6.3746","article-title":"Loss of suppressor of cytokine signaling 1 in helper T cells leads to defective Th17 differentiation by enhancing antagonistic effects of IFN-gamma on STAT3 and Smads","volume":"180","author":"Tanaka","year":"2008","journal-title":"J. Immunol."},{"key":"2025032411461351400_r39","doi-asserted-by":"crossref","first-page":"97","DOI":"10.4049\/jimmunol.0801986","article-title":"TGF-beta promotes Th17 cell development through inhibition of SOCS3","volume":"183","author":"Qin","year":"2009","journal-title":"J. Immunol."},{"key":"2025032411461351400_r40","doi-asserted-by":"crossref","first-page":"4295","DOI":"10.4049\/jimmunol.0903418","article-title":"Role of Smad and non-Smad signals in the development of Th17 and regulatory T cells","volume":"184","author":"Lu","year":"2010","journal-title":"J. Immunol."},{"key":"2025032411461351400_r41","doi-asserted-by":"crossref","first-page":"8137","DOI":"10.1073\/pnas.0600666103","article-title":"Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells","volume":"103","author":"Chen","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032411461351400_r42","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1084\/jem.20040685","article-title":"T cells that cannot respond to TGF-beta escape control by CD4(+)CD25(+) regulatory T cells","volume":"201","author":"Fahl\u00e9n","year":"2005","journal-title":"J. Exp. Med."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/185\/4\/2051\/61610154\/1001171.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/185\/4\/2051\/61610154\/1001171.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T22:51:15Z","timestamp":1743202275000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/185\/4\/2051\/7977629"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,8]]},"references-count":42,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2010,8,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1001171","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2010,8]]},"published":{"date-parts":[[2010,8]]}}}