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Despite its profound effects, the underlying pathophysiological mechanisms of RPL remain largely elusive, with few discernible warning signs. Lymphocyte activation gene-3 (LAG-3) is a crucial immune checkpoint that modulates immune responses during infection and tumor. In the present study, we examined the expression of LAG-3 on CD4<jats:sup>+<\/jats:sup>T cells during pregnancy via cytometry by time-of-flight and flow cytometry. Our findings revealed a higher frequency of LAG-3<jats:sup>+<\/jats:sup> decidual CD4<jats:sup>+<\/jats:sup>T (dCD4<jats:sup>+<\/jats:sup>T) cells in response to trophoblasts during normal pregnancy. This specific LAG-3<jats:sup>+<\/jats:sup> subset of dCD4<jats:sup>+<\/jats:sup>T cells was found to produce a greater number of anti-inflammatory cytokines. Notably, blocking LAG-3 was highly effective in inhibiting the production of anti-inflammatory cytokines, which is detrimental to the maintenance of pregnancy. A decrease in the number of LAG-3<jats:sup>+<\/jats:sup>dCD4<jats:sup>+<\/jats:sup>T cells was correlated with miscarriage. Interestingly, the RNA level of LAG-3 (data analyzed from the two published single-cell databases) remained stable in RPL. Palmitoylation might play a role in regulating LAG-3 expression during RPL, as the palmitoylation of LAG-3<jats:sup>+<\/jats:sup>dCD4<jats:sup>+<\/jats:sup>T cells was increased in RPL. Additionally, the general palmitoylation inhibitor 2-bromopalmitate was found to upregulate LAG-3 expression on dCD4<jats:sup>+<\/jats:sup>T cells both <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo.<\/jats:italic> Collectively, these findings highlighted the significant roles of LAG-3 in regulating the function of dCD4<jats:sup>+<\/jats:sup>T cell and maintaining normal pregnancy. Furthermore, they suggested that lower LAG-3 expression on dCD4<jats:sup>+<\/jats:sup>T cells could serve as a potential biomarker for diagnosis of RPL.<\/jats:p>","DOI":"10.1186\/s10020-025-01361-9","type":"journal-article","created":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T13:03:22Z","timestamp":1759151002000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["LAG-3 palmitoylation-inducing dysfunction of decidual CD4+T cells is associated with recurrent pregnancy loss"],"prefix":"10.1186","volume":"31","author":[{"given":"Liyuan","family":"Cui","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengrun","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinhang","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujie","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinfeng","family":"Qian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songcun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,29]]},"reference":[{"key":"1361_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.esmoop.2021.100262","author":"A Andrikopoulou","year":"2021","unstructured":"Andrikopoulou A, Korakiti AM, Apostolidou K, Dimopoulos MA, Zagouri F. 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