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T-cell immunoglobulin mucin-3 (Tim-3) and programmed cell death-1 (PD-1) are important negative immune regulatory molecules involved in viral persistence and tumor metastasis. Here, we demonstrate that Tim-3\n                    <jats:sup>+<\/jats:sup>\n                    PD-1\n                    <jats:sup>+<\/jats:sup>\n                    CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells from decidua greatly outnumbered those from peripheral blood during human early pregnancy. Co-culture of trophoblasts with CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells upregulated PD-1\n                    <jats:sup>+<\/jats:sup>\n                    and\/or Tim-3\n                    <jats:sup>+<\/jats:sup>\n                    immune cells. Furthermore, the population of CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells co-expressing PD-1 and Tim-3 was enriched within the intermediate memory subset in decidua. This population exhibited high proliferative activity and Th2-type cytokine producing capacity. Blockade of Tim-3 and PD-1 resulted in decreased\n                    <jats:italic>in vitro<\/jats:italic>\n                    proliferation and Th2-type cytokine production while increased trophoblast killing and IFN-\n                    <jats:italic>\u03b3<\/jats:italic>\n                    producing capacities of CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells. Pregnant CBA\/J females challenged with Tim-3 and\/or PD-1 blocking antibodies were more susceptible to fetal loss, which was associated with CD8\n                    <jats:sup>+<\/jats:sup>\n                    T-cell dysfunction. Importantly, the number and function of Tim-3\n                    <jats:sup>+<\/jats:sup>\n                    PD-1\n                    <jats:sup>+<\/jats:sup>\n                    CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells in decidua were significantly impaired in miscarriage. These findings underline the important roles of Tim-3 and PD-1 pathways in regulating decidual CD8\n                    <jats:sup>+<\/jats:sup>\n                    T-cell function and maintaining normal pregnancy.\n                  <\/jats:p>","DOI":"10.1038\/cddis.2015.112","type":"journal-article","created":{"date-parts":[[2015,5,7]],"date-time":"2015-05-07T09:02:17Z","timestamp":1430989337000},"page":"e1738-e1738","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":149,"title":["PD-1 and Tim-3 pathways are associated with regulatory CD8+ T-cell function in decidua and maintenance of normal pregnancy"],"prefix":"10.1038","volume":"6","author":[{"given":"S-C","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y-H","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H-L","family":"Piao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"X-W","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y-Y","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y","family":"Tao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M-M","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D-J","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M-R","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,5,7]]},"reference":[{"key":"BFcddis2015112_CR1","doi-asserted-by":"crossref","first-page":"4562","DOI":"10.4049\/jimmunol.151.9.4562","volume":"151","author":"H Lin","year":"1993","unstructured":"Lin H, Mosmann TR, Guilbert L, Tuntipopipat S, Wegmann TG . 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