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However, the precise roles of Tim-3 on macrophages (M\u03c6s) in pregnancy remain unstated. In the current study, we found the higher frequency of Tim-3<jats:sup>+<\/jats:sup> decidual M\u03c6s (dM\u03c6s) in response to trophoblasts. The reduced abundance of Tim-3 on M\u03c6s was accompanied by disordered anti- and pro-inflammatory cytokine profiles in miscarriage. Adoptive transfer of Tim-3<jats:sup>+<\/jats:sup>M\u03c6s, but not Tim-3<jats:sup>\u2212<\/jats:sup>M\u03c6s, relieved murine embryo absorption induced by M\u03c6 depletion. Our flow cytometry results and the extensive microarray analysis confirmed that Tim-3<jats:sup>+<\/jats:sup> and Tim-3<jats:sup>\u2212<\/jats:sup>dM\u03c6s were neither precisely pro-inflammatory (M1) nor anti-inflammatory (M2) M\u03c6s. However, with higher CD132 expression, Tim-3<jats:sup>+<\/jats:sup>dM\u03c6s subset induced Th2 and Treg bias in decidual CD4<jats:sup>+<\/jats:sup>T cells and promoted pregnancy maintenance. Blockade of Tim-3 or CD132 pathways leaded to the dysfunction of maternal-fetal tolerance and increased fetal loss. These findings underscored the important roles of Tim-3 in regulating dM\u03c6 function and maintaining normal pregnancy, and suggested that Tim-3 on M\u03c6s is a potential biomarker for diagnosis of miscarriage. Our study also emphasized the importance of careful consideration of reproductive safety when choosing immune checkpoint blockade therapies in real world clinical care. Though IL-4 treated Tim-3<jats:sup>\u2212<\/jats:sup>M\u03c6s could rescue the fetal resorption induced by M\u03c6 depletion, whether IL-4 represent novel therapeutic strategy to prevent pregnancy loss induced by checkpoint inhibition still needs further research.<\/jats:p>","DOI":"10.1038\/s41419-022-04899-2","type":"journal-article","created":{"date-parts":[[2022,5,12]],"date-time":"2022-05-12T16:10:09Z","timestamp":1652371809000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Tim-3+ decidual M\u03c6s induced Th2 and Treg bias in decidual CD4+T cells and promoted pregnancy maintenance via CD132"],"prefix":"10.1038","volume":"13","author":[{"given":"Mengdie","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengrun","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lanting","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunqin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liyuan","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinfeng","family":"Qian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dajin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6484-4358","authenticated-orcid":false,"given":"Songcun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5307-6784","authenticated-orcid":false,"given":"Meirong","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,5,12]]},"reference":[{"key":"4899_CR1","first-page":"981","volume":"6","author":"E Dimitriadis","year":"2020","unstructured":"Dimitriadis E, Menkhorst E, Saito S, Kutteh WH, Brosens JJ. 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