{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T01:41:45Z","timestamp":1789004505599,"version":"build-2803163510"},"reference-count":52,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T00:00:00Z","timestamp":1757980800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CRC TR128 (Collaborative Research Center Transregio 128)"},{"name":"DFG (German Research Foundation)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The regulation of T cell-mediated immune responses is essential for maintaining immune homeostasis and preventing autoimmune diseases. In multiple sclerosis (MS), impaired immunoregulatory control allows autoreactive T cells to persist, as effector T cells (Teff) display reduced susceptibility to regulatory T cells (Treg). This resistance to Treg-mediated tolerance is linked to altered IL-6 signaling and hyperactivation of protein kinase B (PKB\/c-Akt). However, the mechanisms leading to increased PKB phosphorylation remain poorly understood. Here, we examined the expression of phosphatase and tensin homolog PTEN, a key phosphatase that negatively regulates PKB\/c-Akt activation. We found that PTEN protein expression rapidly declines in activated Teff from MS patients. To clarify whether PTEN downregulation contributes to Treg resistance, we used PTEN-specific siRNA to modulate PTEN expression in Teff from healthy donors. PTEN knockdown resulted in accelerated IL-6 production, enhanced PKB phosphorylation, and reduced responsiveness to Treg-mediated suppression, similar to Treg resistance observed in MS. This study reports disrupted PTEN expression in activated Teff from MS patients. Our findings highlight that PTEN is critical for effective immune regulation of T cells, and suggest its dysregulation contributes to impaired immune tolerance in MS.<\/jats:p>","DOI":"10.3390\/cells14181445","type":"journal-article","created":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T10:06:25Z","timestamp":1758017185000},"page":"1445","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Impaired PTEN Expression in T Cells Drives Resistance to Treg-Mediated Immune Regulation in Multiple Sclerosis"],"prefix":"10.3390","volume":"14","author":[{"given":"Janine","family":"Schl\u00f6der","sequence":"first","affiliation":[{"name":"Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, Langenbeckstr. 1, 55131 Mainz, Germany"},{"name":"ActiTrexx GmbH, c\/o University Medical Center of the Johannes Gutenberg-University, Langenbeckstr. 1, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bettina","family":"Trinschek","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, Langenbeckstr. 1, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4334-4199","authenticated-orcid":false,"given":"Felix","family":"Luessi","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Medical Center of the Johannes Gutenberg-University, Langenbeckstr. 1, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5672-9365","authenticated-orcid":false,"given":"Helmut","family":"Jonuleit","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, Langenbeckstr. 1, 55131 Mainz, Germany"},{"name":"ActiTrexx GmbH, c\/o University Medical Center of the Johannes Gutenberg-University, Langenbeckstr. 1, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/S0092-8674(00)81107-1","article-title":"Multiple sclerosis: A coordinated immunological attack against myelin in the central nervous system","volume":"85","author":"Steinman","year":"1996","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Trinschek, B., Luessi, F., Haas, J., Wildemann, B., Zipp, F., Wiendl, H., Becker, C., and Jonuleit, H. (2013). Kinetics of IL-6 production defines T effector cell responsiveness to regulatory T cells in multiple sclerosis. PLoS ONE, 8.","DOI":"10.1371\/annotation\/0e76c09e-75b2-493a-90fd-cda3187a0888"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"170ra115","DOI":"10.1126\/scitranslmed.3004970","article-title":"In active relapsing-remitting multiple sclerosis, effector T cell resistance to adaptive T(regs) involves IL-6-mediated signaling","volume":"5","author":"Schneider","year":"2013","journal-title":"Sci. Transl. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"16330","DOI":"10.3390\/ijms160716330","article-title":"Interferon-b therapy of multiple sclerosis patients improves the responsiveness of T cells for immune suppression by regulatory T cells","volume":"16","author":"Trinschek","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Schloder, J., Berges, C., Luessi, F., and Jonuleit, H. (2017). Dimethyl fumarate therapy significantly improves the responsiveness of T cells in multiple sclerosis patients for immunoregulation by regulatory T cells. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18020271"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"469","DOI":"10.3109\/03009748809098809","article-title":"Interleukin-6 (IL-6) in synovial fluid and serum of patients with rheumatic diseases","volume":"17","author":"Swaak","year":"1988","journal-title":"Scand. J. Rheumatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1002\/ibd.20148","article-title":"Il-6 signaling in inflammatory bowel disease: Pathophysiological role and clinical relevance","volume":"13","author":"Mudter","year":"2007","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1136\/gut.2009.184176","article-title":"Disease-related expression of the IL6\/STAT3\/SOCS3 signalling pathway in ulcerative colitis and ulcerative colitis-related carcinogenesis","volume":"59","author":"Li","year":"2010","journal-title":"Gut"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1111\/j.1365-2249.2008.03810.x","article-title":"Increased resistance to CD4+CD25hi regulatory T cell-mediated suppression in patients with type 1 diabetes","volume":"154","author":"Lawson","year":"2008","journal-title":"Clin. Exp. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"16975","DOI":"10.1073\/pnas.1315862110","article-title":"STAT3 activation in response to IL-6 is prolonged by the binding of IL-6 receptor to EGF receptor","volume":"110","author":"Wang","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2502","DOI":"10.1016\/j.ejca.2005.08.016","article-title":"The role of IL-6 and STAT3 in inflammation and cancer","volume":"41","author":"Hodge","year":"2005","journal-title":"Eur. J. Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5991","DOI":"10.1038\/sj.onc.1204833","article-title":"Biologic sequelae of interleukin-6 induced PI3-K\/Akt signaling in multiple myeloma","volume":"20","author":"Hideshima","year":"2001","journal-title":"Oncogene"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1002\/ijc.23261","article-title":"Interleukin-6 activates PI3K\/Akt pathway and regulates cyclin A1 to promote prostate cancer cell survival","volume":"122","author":"Wegiel","year":"2008","journal-title":"Int. J. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.it.2007.02.003","article-title":"\u2018Vive La Resistance!\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":"ref_15","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/S0092-8674(00)81780-8","article-title":"Negative regulation of PKB\/Akt-dependent cell survival by the tumor suppressor PTEN","volume":"95","author":"Stambolic","year":"1998","journal-title":"Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1042\/BST20150224","article-title":"The PTEN protein: Cellular localization and post-translational regulation","volume":"44","author":"Leslie","year":"2016","journal-title":"Biochem. Soc. Trans."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1002\/ana.22366","article-title":"Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria","volume":"69","author":"Polman","year":"2011","journal-title":"Ann. Neurol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1550","DOI":"10.1182\/blood-2007-01-069229","article-title":"Human CD4+CD25+ regulatory T cells: Proteome analysis identifies galectin-10 as a novel marker essential for their anergy and suppressive function","volume":"110","author":"Kubach","year":"2007","journal-title":"Blood"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1084\/jem.20031579","article-title":"Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis","volume":"199","author":"Viglietta","year":"2004","journal-title":"J. Exp. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3538","DOI":"10.1182\/blood-2010-12-328187","article-title":"Functional human regulatory T cells fail to control autoimmune inflammation due to PKB\/c-Akt hyperactivation in effector cells","volume":"118","author":"Wehrens","year":"2011","journal-title":"Blood"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Mercadante, E.R., and Lorenz, U.M. (2016). Breaking Free of Control: How Conventional T Cells Overcome Regulatory T Cell Suppression. Front. Immunol., 7.","DOI":"10.3389\/fimmu.2016.00193"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Chen, C.Y., Chen, J., He, L., and Stiles, B.L. (2018). PTEN: Tumor suppressor and metabolic regulator. Front. Endocrinol., 9.","DOI":"10.3389\/fendo.2018.00338"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/B978-0-444-62702-5.00009-3","article-title":"PTEN hamartoma tumor syndrome","volume":"132","author":"Mester","year":"2015","journal-title":"Handb. Clin. Neurol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.ymeth.2015.02.009","article-title":"PTEN: A yin-yang master regulator protein in health and disease","volume":"77\u201378","author":"Pulido","year":"2015","journal-title":"Methods"},{"key":"ref_25","first-page":"2881","article-title":"Loss of PTEN promotes tumor development in malignant melanoma","volume":"63","author":"Stahl","year":"2003","journal-title":"Cancer Res."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Newton, R.H., and Turka, L.A. (2012). Regulation of T cell homeostasis and responses by PTEN. Front. Immunol., 3.","DOI":"10.3389\/fimmu.2012.00151"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1111\/j.1600-065X.2008.00650.x","article-title":"Regulation of T-cell responses by PTEN","volume":"224","author":"Buckler","year":"2008","journal-title":"Immunol. Rev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1021\/acschemneuro.2c00653","article-title":"MAGI2-AS3 and miR-374b-5p as putative regulators of multiple sclerosis via modulating the PTEN\/AKT\/IRF-3\/IFN-b axis: New clinical insights","volume":"14","author":"Kortam","year":"2023","journal-title":"ACS Chem. Neurosci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"15169","DOI":"10.1073\/pnas.1009193107","article-title":"Hyperactivation of nuclear factor of Activated T cells 1 (NFAT1) in T cells attenuates severity of murine autoimmune encephalomyelitis","volume":"107","author":"Ghosh","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"102027","DOI":"10.1016\/j.xcrm.2025.102027","article-title":"T-bet+ CXCR3+ B cells drive hyperreactive B-T cell interactions in multiple sclerosis","volume":"6","author":"Jelcic","year":"2025","journal-title":"Cell Rep. Med."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Lee, S.H., Park, J.S., Byun, J.K., Jhun, J., Jung, K., Seo, H.B., Moon, Y.M., Kim, H.Y., Park, S.H., and Cho, M.L. (2016). PTEN ameliorates autoimmune arthritis through down-regulating STAT3 activation with reciprocal balance of Th17 and Tregs. Sci. Rep., 6.","DOI":"10.1038\/srep34617"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1016\/S1074-7613(01)00134-0","article-title":"T cell-specific loss of PTEN leads to defects in central and peripheral tolerance","volume":"14","author":"Suzuki","year":"2001","journal-title":"Immunity"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1038\/cmi.2017.30","article-title":"The functions of tumor suppressor PTEN in innate and adaptive immunity","volume":"14","author":"Chen","year":"2017","journal-title":"Cell. Mol. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1186\/s13046-018-0898-9","article-title":"Regulation of PTEN expression by noncoding RNAs","volume":"37","author":"Li","year":"2018","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1186\/s12974-019-1590-5","article-title":"Analysis of miRNA signatures in CSF identifies upregulation of miR-21 and miR-146a\/b in patients with multiple sclerosis and active lesions","volume":"16","author":"Reverter","year":"2019","journal-title":"J. Neuroinflammation"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.neulet.2011.08.021","article-title":"Expression and genetic analysis of miRNAs involved in CD4+ cell activation in patients with multiple sclerosis","volume":"504","author":"Fenoglio","year":"2011","journal-title":"Neurosci. Lett."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1002\/eji.200940032","article-title":"Altered expression of miR-17-5p in CD4+ lymphocytes of relapsing-remitting multiple sclerosis patients","volume":"40","author":"Lindberg","year":"2010","journal-title":"Eur. J. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1038\/sj.bjc.6600031","article-title":"Reduced PTEN expression in the pancreas overexpressing transforming growth factor-beta 1","volume":"86","author":"Ebert","year":"2002","journal-title":"Br. J. Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1046\/j.1365-2249.1998.00604.x","article-title":"Blood levels of transforming growth factor-beta 1 (TGF-beta1) are elevated in both relapsing remitting and chronic progressive multiple sclerosis (MS) patients and are further augmented by treatment with interferon-beta 1b (IFN-beta1b)","volume":"113","author":"Nicoletti","year":"1998","journal-title":"Clin. Exp. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1038\/ncb1897","article-title":"TGF-b activates Akt Kinase through a microRNA-dependent amplifying circuit targeting PTEN","volume":"11","author":"Kato","year":"2009","journal-title":"Nat. Cell Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/j.molcel.2010.07.023","article-title":"STAT3 activation of miR-21 and miR-181b-1 via PTEN and CYLD are part of the epigenetic switch linking inflammation to cancer","volume":"39","author":"Iliopoulos","year":"2010","journal-title":"Mol. Cell"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1038\/nrm3330","article-title":"The functions and regulation of the PTEN tumour suppressor","volume":"13","author":"Song","year":"2012","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"5379","DOI":"10.1158\/1078-0432.CCR-13-2661","article-title":"Molecular pathways: Intercellular PTEN and the potential of PTEN restoration therapy","volume":"20","author":"Hopkins","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.chembiol.2017.10.009","article-title":"The Therapeutic Potential of PTEN Modulation: Targeting Strategies from Gene to Protein","volume":"25","author":"McLoughlin","year":"2018","journal-title":"Cell Chem. Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1126\/science.1234907","article-title":"A Secreted PTEN Phosphatase That Enters Cells to Alter Signaling and Survival","volume":"341","author":"Hopkins","year":"2013","journal-title":"Science"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"5406","DOI":"10.1038\/sj.onc.1203918","article-title":"MMAC1\/PTEN Inhibits Cell Growth and Induces Chemosensitivity to Doxorubicin in Human Bladder Cancer Cells","volume":"19","author":"Tanaka","year":"2000","journal-title":"Oncogene"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.tem.2012.11.002","article-title":"PTEN in Cancer, Metabolism, and Aging","volume":"24","author":"Serrano","year":"2013","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1042\/BJ20120098","article-title":"Functional Analysis of the Protein Phosphatase Activity of PTEN","volume":"444","author":"Zhang","year":"2012","journal-title":"Biochem. J."},{"key":"ref_49","first-page":"505","article-title":"PTEN Activity Defines an Axis for Plasticity at Cortico-Amygdala Synapses and Influences Social Behavior","volume":"30","author":"Ouro","year":"2020","journal-title":"Cereb. Cortex"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Schl\u00f6der, J., Shahneh, F., Schneider, F.J., and Wieschendorf, B. (2022). Boosting regulatory T cell function for the treatment of autoimmune diseases\u2014That\u2019s only half the battle!. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.973813"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"102554","DOI":"10.1016\/j.coi.2025.102554","article-title":"Pharmacotherapeutic strategies to promote regulatory T cell function in autoimmunity","volume":"94","author":"Wright","year":"2025","journal-title":"Curr. Opin. Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Schloder, J., Berges, C., Tuettenberg, A., and Jonuleit, H. (2017). Novel concept of CD4-mediated activation of regulatory T cells for the treatment of graft-versus-host disease. Front. Immunol., 8.","DOI":"10.3389\/fimmu.2017.01495"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/18\/1445\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:46:17Z","timestamp":1760035577000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/18\/1445"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,16]]},"references-count":52,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["cells14181445"],"URL":"https:\/\/doi.org\/10.3390\/cells14181445","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,16]]}}}