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The critical role of brain-infiltrating CD8+ T cells in the pathophysiology of CM having been revealed, our investigation focuses on the role of NR2F6, an established immune checkpoint, as a candidate driver of CM pathology. We employed an experimental mouse model of CM based on Plasmodium berghei ANKA (PbA) infection to compare the relative susceptibility of Nr2f6-knock-out and wild-type C57BL6\/N mice. As a remarkable result, Nr2f6 deficiency confers a significant survival benefit. In terms of mechanism, we detected less severe endotheliopathy and, hence, less damage to the blood\u2013brain barrier (BBB), accompanied by decreased sequestered parasites and less cytotoxic T-lymphocytes within the brain, manifesting in a better disease outcome. We present evidence that NR2F6 deficiency renders mice more resistant to experimental cerebral malaria (ECM), confirming a causal and non-redundant role for NR2F6 in the progression of ECM disease. Consequently, pharmacological inhibitors of the NR2F6 pathway could be of use to bolster BBB integrity and protect against CM.<\/jats:p>","DOI":"10.3390\/cells14151162","type":"journal-article","created":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T14:50:03Z","timestamp":1753714203000},"page":"1162","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["NR2F6 as a Disease Driver and Candidate Therapeutic Target in Experimental Cerebral Malaria"],"prefix":"10.3390","volume":"14","author":[{"given":"Victoria E.","family":"Stefan","sequence":"first","affiliation":[{"name":"Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University Salzburg, 5020 Salzburg, Austria"},{"name":"Department of Biosciences and Medical Biology, University of Salzburg, 5020 Salzburg, Austria"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4146-4664","authenticated-orcid":false,"given":"Victoria","family":"Klepsch","sequence":"additional","affiliation":[{"name":"Institute for Cell Genetics, Medical University of Innsbruck, 6020 Innsbruck, Austria"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2253-3946","authenticated-orcid":false,"given":"Nikolaus","family":"Thuille","sequence":"additional","affiliation":[{"name":"Institute for Cell Genetics, Medical University of Innsbruck, 6020 Innsbruck, Austria"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8925-8484","authenticated-orcid":false,"given":"Martina","family":"Steinlechner","sequence":"additional","affiliation":[{"name":"Institute for Cell Genetics, Medical University of Innsbruck, 6020 Innsbruck, Austria"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4372-5365","authenticated-orcid":false,"given":"Sebastian","family":"Peer","sequence":"additional","affiliation":[{"name":"Internal Medicine V (Hematology and Oncology), Medical University of Innsbruck, 6020 Innsbruck, Austria"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3654-1170","authenticated-orcid":false,"given":"Kerstin","family":"Siegmund","sequence":"additional","affiliation":[{"name":"Institute for Cell Genetics, Medical University of Innsbruck, 6020 Innsbruck, Austria"}]},{"given":"Peter","family":"Lackner","sequence":"additional","affiliation":[{"name":"Vienna Healthcare Group, Department of Neurology, Klinik Floridsdorf, 1010 Vienna, Austria"},{"name":"Karl-Landsteiner-Institute for Clinical Research in Acute Neurology, 1010 Vienna, Austria"}]},{"given":"Erich","family":"Schmutzhard","sequence":"additional","affiliation":[{"name":"Department of Neurology, Medical University of Innsbruck, 6020 Innsbruck, Austria"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0336-7130","authenticated-orcid":false,"given":"Karin","family":"Albrecht-Schg\u00f6r","sequence":"additional","affiliation":[{"name":"Institute for Cell Genetics, Medical University of Innsbruck, 6020 Innsbruck, Austria"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2085-8325","authenticated-orcid":false,"given":"Gottfried","family":"Baier","sequence":"additional","affiliation":[{"name":"Institute for Cell Genetics, Medical University of Innsbruck, 6020 Innsbruck, Austria"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"100085","DOI":"10.1016\/j.gpeds.2023.100085","article-title":"Age-specific malaria vulnerability and transmission reservoir among children","volume":"6","author":"Ranjha","year":"2023","journal-title":"Glob. 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