Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, China Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China.
Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, China Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China
Hum Reprod. 2016 Apr;31(4):700-11. doi: 10.1093/humrep/dew019. Epub 2016 Feb 16.
Are the immune regulatory molecules programmed cell death-1 (PD-1) and T-cell immunoglobulin mucin-3 (Tim-3) involved in regulating CD4+ T cell function during pregnancy?
PD-1 and Tim-3 promote Type 2 helper T cell (Th2) bias and pregnancy maintenance by regulating CD4+ T cell function at the maternal-fetal interface.
The maternal CD4+ T cell response to fetal antigens is thought to be an important component of maternal-fetal tolerance during pregnancy. PD-1 and Tim-3 are important for limiting immunopathology. The co-expression of PD-1 and Tim-3 on T cells identifies a T cell subset with impaired proliferation and cytokine production. Combined blockade of Tim-3 and PD-1 could restore T cell function to the greatest degree.
STUDY DESIGN, SIZE, DURATION: The expression of PD-1 and Tim-3 on CD4+ T cells was analyzed by flow cytometry, and in vitro and in vivo analyses were used to investigate the role of PD-1/Tim-3 signal in the regulation of CD4+ T cells function and pregnancy outcome.
PARTICIPANTS/ MATERIALS, SETTING, METHODS: A total of 88 normal pregnant women, 37 women with recurrent spontaneous abortion, 36 normal pregnant mice and 45 abortion-prone mice were included. We measure the expression of PD-1 and Tim-3 on CD4+ T cells and their relationship to the function of CD4+ T cells and pregnancy outcome, as well as the effects of blocking PD-1 and Tim-3 pathways on decidual CD4+ T (dCD4+ T) cells during early pregnancy.
PD-1 and Tim-3, by virtue of their up-regulation on dCD4+ T cells during pregnancy, define a specific effector/memory subset of CD4+ T cells and promote Th2 bias at the maternal-fetal interface. Using in vitro and in vivo experiments, we also found that combined targeting of PD-1 and Tim-3 pathways results in decreased production of Th2-type cytokines by dCD4+ T cells and increased fetal resorption of normal pregnant murine models. Moreover, decreased PD-1 and Tim-3 on dCD4+ T cells may be associated with miscarriage.
Further study is required to examine the mechanism of PD-1 and Tim-3 effects on Th2 cytokine production by CD4+ T cells during pregnancy.
These results have important implications for understanding the physiological mechanisms that promote maternal-fetal tolerance. Our study also indicates that targeting Tim-3 and PD-1 pathways may represent novel therapeutic strategies to prevent pregnancy loss.
STUDY FUNDING/COMPETING INTERESTS: This study was supported by the National Basic Research Program of China (2015CB943300); National Nature Science Foundation of China (81490744, 91542116, 31570920, 81070537, 31171437, 81370770, 31270969, 31570920, 91542116); the Key Project of Shanghai Municipal Education Commission (14ZZ013) and the Key Project of Shanghai Basic Research from Shanghai Municipal Science and Technology Commission (12JC1401600). None of the authors have any conflict of interest to declare.
程序性细胞死亡蛋白-1（PD-1）和 T 细胞免疫球蛋白黏蛋白-3（Tim-3）等免疫调节分子是否参与妊娠期间 CD4+T 细胞功能的调节？
PD-1 和 Tim-3 通过调节母胎界面 CD4+T 细胞功能，促进 2 型辅助性 T 细胞（Th2）偏向和妊娠维持。
人们认为母体 CD4+T 细胞对胎儿抗原的反应是妊娠期间母体-胎儿耐受的重要组成部分。PD-1 和 Tim-3 对于限制免疫病理非常重要。T 细胞上 PD-1 和 Tim-3 的共表达鉴定了具有受损增殖和细胞因子产生能力的 T 细胞亚群。联合阻断 Tim-3 和 PD-1 可以最大程度地恢复 T 细胞功能。
研究设计、规模、持续时间：通过流式细胞术分析 PD-1 和 Tim-3 在 CD4+T 细胞上的表达，并进行体外和体内分析，研究 PD-1/Tim-3 信号在调节 CD4+T 细胞功能和妊娠结局中的作用。
参与者/材料、设置、方法：共纳入 88 例正常孕妇、37 例复发性自然流产患者、36 例正常妊娠小鼠和 45 例易流产小鼠。我们测量了 PD-1 和 Tim-3 在 CD4+T 细胞上的表达及其与 CD4+T 细胞功能和妊娠结局的关系，以及阻断 PD-1 和 Tim-3 途径对早孕蜕膜 CD4+T（dCD4+T）细胞的影响。
PD-1 和 Tim-3 通过其在妊娠期间 dCD4+T 细胞上的上调，定义了 CD4+T 细胞的特定效应/记忆亚群，并促进母胎界面 Th2 偏向。通过体外和体内实验，我们还发现，联合靶向 PD-1 和 Tim-3 途径会导致 dCD4+T 细胞产生的 Th2 型细胞因子减少，并增加正常妊娠小鼠模型的胎儿吸收。此外，dCD4+T 细胞上 PD-1 和 Tim-3 的减少可能与流产有关。
需要进一步研究以检查 PD-1 和 Tim-3 对妊娠期间 CD4+T 细胞产生 Th2 细胞因子的影响机制。
这些结果对于理解促进母体-胎儿耐受的生理机制具有重要意义。我们的研究还表明，靶向 Tim-3 和 PD-1 途径可能代表预防妊娠丢失的新治疗策略。
研究资金/利益冲突：本研究得到了中国国家基础研究计划（2015CB943300）、中国国家自然科学基金（81490744、91542116、31570920、81070537、31771437、81370770、31270969、31570920、91542116）、上海市教育委员会重点项目（14ZZ013）和上海市科学技术委员会基础研究重点项目（12JC1401600）的支持。作者均无利益冲突。
