{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T07:24:18Z","timestamp":1771917858081,"version":"3.50.1"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2022,10,1]],"date-time":"2022-10-01T00:00:00Z","timestamp":1664582400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100007028","name":"Leona M. and Harry B. Helmsley Charitable Trust","doi-asserted-by":"publisher","award":["1911-03444"],"award-info":[{"award-number":["1911-03444"]}],"id":[{"id":"10.13039\/100007028","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007028","name":"Leona M. and Harry B. Helmsley Charitable Trust","doi-asserted-by":"publisher","award":["1911-03444"],"award-info":[{"award-number":["1911-03444"]}],"id":[{"id":"10.13039\/100007028","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Cbl-b is a negative regulator of T cell activation, and in murine models, a lack of Cblb results in resistance of T effector (Teff) cells to T regulatory (Treg) cells, a feature of T cells in many autoimmune diseases. Here, we used trackable gene editing approaches to knock out CBLB in primary human CD4+ T cells. We found that CBLB-knockout (CBLB-KO) CD4+ T cells were hyperproliferative and produced excessive amounts of IL-2. CBLB-KO CD4+ T cells were resistant to Treg suppression in vitro, which was partially reversed by blockade of IL-2. RNA-sequencing and puromycin incorporation assays demonstrated that CBLB-KO CD4+ T cells can overcome Treg suppression on the transcriptional and translational levels, resulting in the overproduction of cytokines to drive the proliferation and activation of Teff cells. These findings highlight a potential mechanism of Teff resistance in human autoimmune disease and the power of gene editing primary T cells to explore disease mechanisms.<\/jats:p>","DOI":"10.4049\/jimmunol.2200219","type":"journal-article","created":{"date-parts":[[2022,10,20]],"date-time":"2022-10-20T17:47:26Z","timestamp":1666288046000},"page":"1260-1271","source":"Crossref","is-referenced-by-count":3,"title":["<i>CBLB<\/i> Deficiency in Human CD4+ T Cells Results in Resistance to T Regulatory Suppression through Multiple Mechanisms"],"prefix":"10.1093","volume":"209","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3319-9063","authenticated-orcid":false,"given":"Jing","family":"Song","sequence":"first","affiliation":[{"name":"Center for Translational Immunology, Benaroya Research Institute at Virginia Mason , Seattle, WA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9315-5233","authenticated-orcid":false,"given":"Warren","family":"Anderson","sequence":"additional","affiliation":[{"name":"Center for Immunity and Immunotherapies and the Program for Cell and Gene Therapy, Seattle Children\u2019s Research Institute , Seattle, WA"},{"name":"Department of Pathology, University of Washington School of Medicine , Seattle, WA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6846-1776","authenticated-orcid":false,"given":"Alex","family":"Hu","sequence":"additional","affiliation":[{"name":"Center for Systems Immunology, Benaroya Research Institute at Virginia Mason , Seattle, WA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0984-6518","authenticated-orcid":false,"given":"Kazushige","family":"Obata-Ninomiya","sequence":"additional","affiliation":[{"name":"Center for Fundamental Immunology, Benaroya Research Institute at Virginia Mason , Seattle, WA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven F","family":"Ziegler","sequence":"additional","affiliation":[{"name":"Center for Fundamental Immunology, Benaroya Research Institute at Virginia Mason , Seattle, WA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David J","family":"Rawlings","sequence":"additional","affiliation":[{"name":"Center for Immunity and Immunotherapies and the Program for Cell and Gene Therapy, Seattle Children\u2019s Research Institute , Seattle, WA"},{"name":"Department of Pediatrics, University of Washington School of Medicine , Seattle, WA"},{"name":"Department of Immunology, University of Washington School of Medicine , Seattle, WA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9005-1885","authenticated-orcid":false,"given":"Jane H","family":"Buckner","sequence":"additional","affiliation":[{"name":"Center for Translational Immunology, Benaroya Research Institute at Virginia Mason , Seattle, WA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2022,10,1]]},"reference":[{"key":"2025021008324225200_r1","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. 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Immunol."},{"key":"2025021008324225200_r4","doi-asserted-by":"crossref","first-page":"356ra119","DOI":"10.1126\/scitranslmed.aad9943","article-title":"Enhanced T cell responses to IL-6 in type 1 diabetes are associated with early clinical disease and increased IL-6 receptor expression","volume":"8","author":"Hundhausen","year":"2016","journal-title":"Sci. Transl. Med."},{"key":"2025021008324225200_r5","doi-asserted-by":"crossref","first-page":"170ra15","DOI":"10.1126\/scitranslmed.3004970","article-title":"In active relapsing-remitting multiple sclerosis, effector T cell resistance to adaptive Tregs involves IL-6\u2013mediated signaling","volume":"5","author":"Schneider","year":"2013","journal-title":"Sci. Transl. Med."},{"key":"2025021008324225200_r6","doi-asserted-by":"crossref","first-page":"e77634","DOI":"10.1371\/journal.pone.0077634","article-title":"Kinetics of IL-6 production defines T effector cell responsiveness to regulatory T cells in multiple sclerosis. [Published erratum appears in 2013 PLoS One 8(11).]","volume":"8","author":"Trinschek","year":"2013","journal-title":"PLoS One"},{"key":"2025021008324225200_r7","doi-asserted-by":"crossref","first-page":"2180","DOI":"10.4049\/jimmunol.1303257","article-title":"Nonapoptotic and extracellular activity of granzyme B mediates resistance to regulatory T cell (Treg) suppression by HLA-DR\u2212CD25hiCD127lo Tregs in multiple sclerosis and in response to IL-6","volume":"194","author":"Bhela","year":"2015","journal-title":"J. Immunol."},{"key":"2025021008324225200_r8","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1177\/0961203307088307","article-title":"Quantitative and qualitative normal regulatory T cells are not capable of inducing suppression in SLE patients due to T-cell resistance","volume":"17","author":"Vargas-Rojas","year":"2008","journal-title":"Lupus"},{"key":"2025021008324225200_r9","doi-asserted-by":"crossref","first-page":"2120","DOI":"10.1002\/art.23556","article-title":"Reduced CD4+,CD25\u2212 T cell sensitivity to the suppressive function of CD4+,CD25high,CD127\u2212\/low regulatory T cells in patients with active systemic lupus erythematosus","volume":"58","author":"Chowdary Venigalla","year":"2008","journal-title":"Arthritis Rheum."},{"key":"2025021008324225200_r10","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":"2025021008324225200_r11","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":"2025021008324225200_r12","doi-asserted-by":"crossref","first-page":"1472","DOI":"10.4049\/jimmunol.174.3.1472","article-title":"Differential control of CD28-regulated in vivo immunity by the E3 ligase Cbl-b","volume":"174","author":"Krawczyk","year":"2005","journal-title":"J. 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