PDL1 blockage increases fetal resorption and Tfr cells but does not affect Tfh/Tfr ratio and B-cell maturation during allogeneic pregnancy.,Cell Death & Disease

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PDL1 blockage increases fetal resorption and Tfr cells but does not affect Tfh/Tfr ratio and B-cell maturation during allogeneic pregnancy.
Cell Death & Disease ( IF 8.1 ) Pub Date : 2020-02-12 , DOI: 10.1038/s41419-020-2313-7
Weihong Zeng ₁ , Shi Qin ₁ , Renjie Wang ₂ , Yuchen Zhang ₁ , Xiaoling Ma ₁ , Fuju Tian ₁ , Xiao-Rui Liu ₁ , Xiaoli Qin ₁ , Shujie Liao ₂ , Liqun Sun ₁ , Yi Lin ₁

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A successful pregnancy requires sophisticated regulation of uterine microenvironment to guarantee the existence of semi-allogeneic conceptus without immune rejection. T follicular regulatory (Tfr) cells exert a suppressive effect on Tfh-cell expansion, B-cell response, and antibody production. Although accumulating evidence has demonstrated that dysregulations of Tfr cells can bring on various immunological diseases, their immunomodulatory roles during pregnancy still remain unheeded. Herein, we introduced an allogeneic normal-pregnant mouse model and found that CD4+CXCR5hiPD-1hiFoxp3+ Tfr cells were preferentially accumulated in the uterus at mid-gestation and displayed a distinct phenotype. In addition, the absence of PDL1 resulted in increased fetal resorption by favoring Tfr cells accumulation and upregulating PD-1 expression on these cells. However, PDL1 blockade affected neither the ratio of Tfh/Tfr cells nor the maturation and differentiation of B cells. Overall, our results are the first to present a correlation of Tfr cells accumulation with healthy allogeneic pregnancy and PDL1 blockade-induced miscarriage, and to indicate that appropriate assembly of Tfr cells is important for pregnancy maintenance. Since blockade of PD-1-PDL1 pathway leads to more Tfr cells and fetal losses, the reproductive safety must be taken into consideration when PD-1/PD-L1 checkpoint blockade immunotherapy is used in pregnancy.

中文翻译：

PDL1阻滞增加了胎儿的吸收和Tfr细胞，但不影响同种异体妊娠期间的Tfh / Tfr比值和B细胞成熟。

成功的妊娠需要对子宫微环境进行精密的调节，以确保存在半同种异体妊娠而无免疫排斥。T滤泡调节（Tfr）细胞对Tfh细胞扩增，B细胞反应和抗体产生具有抑制作用。尽管越来越多的证据表明，Tfr细胞功能失调会引起多种免疫疾病，但它们在怀孕期间的免疫调节作用仍然未被人们注意。在这里，我们引入了同种异体正常怀孕小鼠模型，发现CD4 + CXCR5hiPD-1hiFoxp3 + Tfr细胞在妊娠中期优先聚集在子宫中并表现出独特的表型。此外，PDL1的缺失通过促进Tfr细胞积累并上调这些细胞上PD-1的表达而导致胎儿的吸收增加。但是，PDL1封锁既不影响Tfh / Tfr细胞的比率，也不影响B细胞的成熟和分化。总的来说，我们的结果是第一个显示Tfr细胞积累与健康同种异体妊娠和PDL1阻断引起的流产的相关性，并表明适当组装Tfr细胞对于维持妊娠很重要。由于阻断PD-1-PDL1途径会导致更多的Tfr细胞和胎儿流失，因此在妊娠中使用PD-1 / PD-L1检查点阻断免疫疗法时必须考虑生殖安全性。并指出适当组装Tfr细胞对于维持妊娠很重要。由于阻断PD-1-PDL1途径会导致更多的Tfr细胞和胎儿流失，因此在妊娠中使用PD-1 / PD-L1检查点阻断免疫疗法时必须考虑生殖安全性。并指出适当组装Tfr细胞对于维持妊娠很重要。由于阻断PD-1-PDL1途径会导致更多的Tfr细胞和胎儿流失，因此在妊娠中使用PD-1 / PD-L1检查点阻断免疫疗法时必须考虑生殖安全性。

更新日期：2020-02-12

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