Transplantation Research Center, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
J Immunol. 2013 Jan 1;190(1):88-96. doi: 10.4049/jimmunol.1202176. Epub 2012 Nov 23.
TIM-3 is constitutively expressed on subsets of macrophages and dendritic cells. Its expression on other cells of the innate immune system and its role in fetomaternal tolerance has not yet been explored. In this study, we investigate the role of TIM-3-expressing innate immune cells in the regulation of tolerance at the fetomaternal interface (FMI) using an allogeneic mouse model of pregnancy. Blockade of TIM-3 results in accumulation of inflammatory granulocytes and macrophages at the uteroplacental interface and upregulation of proinflammatory cytokines. Furthermore, TIM-3 blockade inhibits the phagocytic potential of uterine macrophages resulting in a build up of apoptotic bodies at the uteroplacental interface that elicits a local immune response. In response to inflammatory cytokines, Ly-6C(hi)G(neg) monocytic myeloid-derived suppressor cells expressing inducible NO synthase and arginase 1 are induced. However, these suppressive cells fail to downregulate the inflammatory cascade induced by inflammatory granulocytes (Ly-6C(int)G(hi)) and apoptotic cells; the increased production of IFN-γ and TNF-α by inflammatory granulocytes leads to abrogation of tolerance at the FMI and fetal rejection. These data highlight the interplay between cells of the innate immune system at the FMI and their influence on successful pregnancy in mice.
TIM-3 在巨噬细胞和树突状细胞的亚群上持续表达。其在先天免疫系统其他细胞上的表达及其在胎儿母体耐受中的作用尚未被探索。在这项研究中，我们使用同种异体妊娠小鼠模型，研究了表达 TIM-3 的先天免疫细胞在胎儿母体界面（FMI）调节耐受中的作用。TIM-3 阻断导致炎症性粒细胞和巨噬细胞在子宫胎盘界面积聚，并上调促炎细胞因子。此外，TIM-3 阻断抑制了子宫巨噬细胞的吞噬能力，导致在子宫胎盘界面形成凋亡小体，引发局部免疫反应。针对炎症细胞因子，诱导型一氧化氮合酶和精氨酸酶 1 表达的 Ly-6C(hi)G(neg)单核细胞髓系来源的抑制细胞被诱导。然而，这些抑制细胞未能下调炎症粒细胞（Ly-6C(int)G(hi)）和凋亡细胞诱导的炎症级联；炎症粒细胞增加 IFN-γ 和 TNF-α 的产生导致 FMI 耐受的丧失和胎儿排斥。这些数据强调了先天免疫系统细胞在 FMI 中的相互作用及其对小鼠成功妊娠的影响。
