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However, the phenotype of LAG3\u207aCD4\u207a T cells during\n                      <jats:italic>Plasmodium<\/jats:italic>\n                      infection and the upstream molecular mechanisms regulating LAG3 expression remain incompletely elucidated.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We established a murine model using\n                      <jats:italic>Plasmodium yoelii<\/jats:italic>\n                      NSM (\n                      <jats:italic>P. yoelii<\/jats:italic>\n                      NSM). A multifaceted approach, incorporating single-cell RNA sequencing (scRNA-seq), flow cytometry, magnetic bead-based cell sorting, real-time quantitative polymerase chain reaction (RT\u2013qPCR), dual-luciferase reporter assays, and in vitro cultures with the Wnt agonist CHIR99021, was employed. We characterized splenic CD4\u207a T cell dynamics, the phenotypic and functional profiles of LAG3\u207aCD4\u207a T cells, and the transcriptional regulatory relationship between lymphoid enhancer-binding factor 1 (LEF1) and\n                      <jats:italic>Lag3<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Plasmodium yoelii<\/jats:italic>\n                      NSM infection induced significant splenomegaly and remodeling of the splenic CD4\u207a T cell compartment, with increased absolute numbers of CD4\u207a T cells, upregulated activation markers (ICOS, CD69), downregulated na\u00efve marker CD62L, and enhanced secretion of IL-10 and IFN-\u03b3. Both scRNA-seq and flow cytometry confirmed that infection markedly upregulated LAG3 on CD4\u207a T cells. These LAG3\u207aCD4\u207a T cells exhibited an activated phenotype, characterized by increased proliferative capacity (Ki67\u207a), an increased proportion of the effector phenotype (CD44\u02b0\u2071CD62L\u02e1\u1d52), and concurrent upregulation of multiple co-inhibitory receptors (PD-1, TIM-3, TIGIT). Mechanistically, LEF1 expression was significantly downregulated in CD4\u207a T cells post infection. Dual-luciferase reporter assay demonstrated that LEF1 directly binds to the\n                      <jats:italic>Lag3<\/jats:italic>\n                      promoter, acting as a transcriptional repressor. Furthermore, treatment with the Wnt agonist CHIR99021, which stabilizes the upstream signaling of LEF1, dose-dependently reduced the frequency of LAG3\u207aCD4\u207a T cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      This study suggests that the LEF1\u2013LAG3 axis is involved in modulating CD4\u207a T cells during\n                      <jats:italic>P. yoelii<\/jats:italic>\n                      NSM infection. LAG3\u207aCD4\u207a T cells exhibit an activated phenotype with regulatory potential, which may contribute to balancing anti-parasitic immunity and immunopathology. These findings suggest that modulating LEF1-mediated transcriptional repression of\n                      <jats:italic>Lag3<\/jats:italic>\n                      offers a promising avenue for fine-tuning anti-malarial immune responses.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13071-026-07439-5","type":"journal-article","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T16:36:21Z","timestamp":1779813381000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The LEF1\u2013LAG3 axis regulates CD4+ T cell function during Plasmodium yoelii NSM infection"],"prefix":"10.1186","volume":"19","author":[{"given":"Wenbo","family":"Peng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guikuan","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keyu","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Mo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiongyu","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingjie","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiwen","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lixin","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingyue","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Long","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haixia","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyan","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingfei","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,26]]},"reference":[{"key":"7439_CR1","unstructured":"WHO. 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