{
  "abstract": "Although nuclear receptor subfamily 2 group F member 6 (NR2F6) regulates lymphocyte activation in murine models, its function in human T cells remains incompletely defined. Here, we identify NR2F6 as a T cell receptor (TCR)-inducible transcriptional checkpoint that limits effector potency in human CD3+ T cells, including chimeric antigen receptor (CAR) T cells. In an anti-EGFR CAR-T cell-A549 co-culture model, enforced NR2F6 expression, mimicking its upregulation in tumor-infiltrating lymphocytes, markedly impairs killing under repeated tumor challenge. In polyclonal T cells, NR2F6 overexpression and CRISPR-Cas9-mediated ablation produced directionally opposing effects, supporting its role as a negative regulator of activation, differentiation-associated programs, and cytokine production. Mechanistically, transcriptomic, epigenomic, and nuclear protein analyses are consistent with suppression of NFAT-, AP-1-, and NF-κB-associated pathways and reveal context-dependent changes in TCF-1-associated readouts. Collectively, these findings position NR2F6 as a signaling-integrated transcriptional checkpoint that contributes to dysfunctional T cell states and may promote tumor immune evasion in humans.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": "Article",
  "arxiv": null,
  "author_total": 14,
  "authors": [
    {
      "name": "Jiří Koutník",
      "orcid": "0000-0003-0904-0968"
    },
    {
      "name": "Thomas Gruber"
    },
    {
      "name": "Dorothee Freimark"
    },
    {
      "name": "Dominik Humer",
      "orcid": "0009-0008-2167-9346"
    },
    {
      "name": "Daniel Schreiber",
      "orcid": "0009-0004-7507-9603"
    },
    {
      "name": "Isabel Hölzl"
    },
    {
      "name": "Viktor Lang"
    },
    {
      "name": "Nino Tokic"
    },
    {
      "name": "Tajana Sajinovic"
    },
    {
      "name": "Dominik Wolf"
    },
    {
      "name": "Nikolaus Thuille",
      "orcid": "0000-0002-2253-3946"
    },
    {
      "name": "Kerstin Siegmund"
    },
    {
      "name": "Victoria Klepsch"
    },
    {
      "name": "Gottfried Baier",
      "orcid": "0000-0002-2085-8325"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/9a7vh4wh5ekt0.bib",
  "cited_by": 0,
  "doi": "10.1016/j.isci.2026.117982",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13734946/",
  "id": "9a7vh4wh5ekt0",
  "issns": [
    "2589-0042"
  ],
  "landing_url": "https://www.cell.com/iscience/fulltext/S2589-0042(26)03365-1",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "http://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Article"
    ],
    [
      "heading",
      "Cell biology"
    ],
    [
      "heading",
      "Immunology"
    ],
    [
      "openalex",
      "2403|T-cell and B-cell Immunology"
    ]
  ],
  "openalex": "W7223706685",
  "pdf_url": null,
  "pmcid": "PMC13734946",
  "pmid": "42990653",
  "published": "2026-10-26",
  "publisher": "Elsevier BV",
  "ris": "https://research.draconitic.com/paper/9a7vh4wh5ekt0.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:16Z",
      "native_id": "10.1016/j.isci.2026.117982",
      "source": "feed-cell",
      "url": "https://www.cell.com/iscience/fulltext/S2589-0042(26)03365-1"
    },
    {
      "first_seen": "2026-10-30T12:17:49Z",
      "native_id": "10.1016/j.isci.2026.117982",
      "source": "crossref",
      "url": "https://linkinghub.elsevier.com/retrieve/pii/S2589004226033651"
    },
    {
      "first_seen": "2026-11-09T12:20:44Z",
      "native_id": "PMC13734946",
      "source": "pmc",
      "url": "https://doi.org/10.1016/j.isci.2026.117982"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "heading:Cell biology",
      "subfield": "cell-biology"
    },
    {
      "field": "biology",
      "origin": "heading:Immunology",
      "subfield": "immunology"
    }
  ],
  "title": "NR2F6 functions as a key transcriptional checkpoint enforcing dysfunction of human CD3+ T cells and limiting CAR-T cell potency",
  "title_text": "NR2F6 functions as a key transcriptional checkpoint enforcing dysfunction of human CD3+ T cells and limiting CAR-T cell potency",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T12:20:44Z",
  "url": "https://research.draconitic.com/paper/9a7vh4wh5ekt0",
  "venue": "iScience",
  "versions": []
}