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CD8\u2009\u207a\u2009T cells are known to play a key role in anti-malaria immunity. Lymphocyte Activation Gene 3 (LAG3), a critical immune checkpoint molecule, is pivotal in CD8\u2009\u207a\u2009T cell-mediated anti-tumor responses. However, the role of LAG3\u2009\u207a\u2009CD8\u2009\u207a\u2009T cells in anti-malarial immunity and the regulatory factors governing LAG3 expression in CD8\u2009\u207a\u2009T cells remain unclear. In this study, C57BL\/6 mice were subcutaneously infected with\n                    <jats:italic>\n                      <jats:italic>Plasmodium yoelii<\/jats:italic>\n                    <\/jats:italic>\n                    NSM. Splenic lymphocytes were isolated and analyzed using flow cytometry (FACs) and single-cell RNA sequencing (scRNA-seq). Results showed a significant upregulation of LAG3 expression in splenic CD8\u2009\u207a\u2009T cells post-infection. These LAG3\u2009\u207a\u2009CD8\u2009\u207a\u2009T cells displayed enhanced activation, responsiveness, proliferative capacity, and cytokine production. Additionally, activated nuclear factor of activated T cells 1 (NFATc1) was found to co-express with LAG3 in splenic CD8\u2009\u207a\u2009T cells from infected mice. Dual-fluorescence reporter gene assays in 293T cells identified NFATc1 as a key transcription factor that binds to the LAG3 promoter sequence. Knockdown of NFATc1\n                    <jats:italic>\n                      <jats:italic>via<\/jats:italic>\n                    <\/jats:italic>\n                    small interfering RNA (siRNA) reduced LAG3 expression. In conclusion, our findings suggest that splenic LAG3\u2009\u207a\u2009CD8\u2009\u207a\u2009T cells in\n                    <jats:italic>\n                      <jats:italic>Plasmodium yoelii<\/jats:italic>\n                    <\/jats:italic>\n                    NSM-infected C57BL\/6 mice display enhanced functionality and imply that NFATc1 could positively regulate LAG3 expression.\n                  <\/jats:p>","DOI":"10.1371\/journal.pntd.0013605","type":"journal-article","created":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T17:40:18Z","timestamp":1759772418000},"page":"e0013605","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["NFATc1 regulates LAG3+CD8+ T cells in the spleen of mice infected with Plasmodium yoelii 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