The appropriate frequency and function of decidual Tim-3+CTLA-4+CD8+ T cells are important in maintaining normal pregnancy
The appropriate frequency and function of decidual Tim-3+CTLA-4+CD8+ T cells are important in maintaining normal pregnancy
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蜕膜 Tim-3( )CTLA-4( )CD8( ) T 细胞的适当频率和功能对于维持正常妊娠非常重要
DOI：
10.1038/s41419-019-1642-x
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发表时间：
2019-05-28
影响因子：
9
通讯作者：
Du，Meirong
中科院分区：
文献类型：
--
作者：
Wang，Songcun;Sun，Fengrun;Du，Meirong
母体蜕膜CD 8 +T（dCD 8 +T）细胞必须整合母胎耐受和抗病毒免疫的对立需求，以建立成功的妊娠。T细胞免疫球蛋白粘蛋白3（Tim-3）和细胞毒性T淋巴细胞相关蛋白4（CTLA-4）是两种重要的共抑制分子，在感染和肿瘤过程中调节CD 8 +T细胞的反应。在本研究中，我们检测了妊娠期间Tim-3和CTLA-4在CD 8 +T细胞上的共表达，发现Tim-3+CTLA-4+ dCD 8 +T细胞响应滋养层细胞的频率更高。这种Tim-3+CTLA-4+ dCD 8 +T细胞亚群显示出活跃状态，并产生更多的抗炎细胞因子。此外，Tim-3+CTLA-4+ dCD 8 +T细胞的数量减少和功能改变与流产相关。联合阻断Tim-3和CTLA-4通路在抑制抗炎细胞因子的产生方面非常有效，并且不利于妊娠的维持。这些结果支持Tim-3和CTLA-4通路可能在母胎耐受的建立和/或维持中发挥积极作用，从而促进正常妊娠的维持。因此，在妊娠期使用抗Tim-3/CTLA-4抗体（以及其他免疫检查点抑制剂）时，必须考虑生殖安全性。
Maternal decidual CD8+T (dCD8+T) cells must integrate the antithetical demands of maternal–fetal tolerance and anti-viral immunity to establish a successful pregnancy. T-cell immunoglobulin mucin-3 (Tim-3) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are two important co-inhibitory molecules that regulating CD8+T cells responses during infection and tumor. In the present study, we examined the co-expression of Tim-3 and CTLA-4 on CD8+T cells during pregnancy and found the higher frequency of Tim-3+CTLA-4+dCD8+T cells in response to trophoblasts. This Tim-3+CTLA-4+dCD8+T cells subset showed an active status and produced more anti-inflammatory cytokines. Furthermore, the decreased number and altered function of Tim-3+CTLA-4+dCD8+T cells correlated to miscarriage. Combined blocking Tim-3 and CTLA-4 pathways were highly effective in inhibiting the production of anti-inflammatory cytokines and were detrimental to the maintenance of pregnancy. Together, these findings supported that Tim-3 and CTLA-4 pathways might play positive roles in the establishment and/or maintenance of maternal–fetal tolerance so to promote the maintenance of normal pregnancy. So the reproductive safety must be considered, especially when anti-Tim-3/CTLA-4 antibody (and other immune checkpoint inhibitors) are used in pregnancy.