Department of Assisted Reproduction, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Biophysics, College of Basic Medical Sciences, Second Military Medical University, Shanghai, China.
Front Immunol. 2021 Mar 25;12:649135. doi: 10.3389/fimmu.2021.649135. eCollection 2021.
The perfect synchronization of maternal immune-endocrine mechanisms and those of the fetus is necessary for a successful pregnancy. In this report, decidual immune cells at the maternal-fetal interface were detected that expressed TIGIT (T cell immunoreceptor with Ig and ITIM domains), which is a co-inhibitory receptor that triggers immunological tolerance. We generated recombinant TIGIT-Fc fusion proteins by linking the extracellular domain of TIGIT and silent Fc fragments. The treatment with TIGIT-Fc of human decidual antigen presenting cells (APCs), the decidual dendritic cells (dDCs), and decidual macrophages (dMϕs) increased the production of interleukin 10 and induced the decidua APCs to powerfully polarize the decidual CD4 T cells toward a classic T2 phenotype. We further proposed that Notch signaling shows a pivotal effect on the transcriptional regulation in decidual immune cell subsets. Moreover, the administration of TIGIT-Fc to CBA/J pregnant mice at preimplantation induced CD4 forkhead box P3 (Foxp3) regulatory T cells and tolerogenic dendritic cells and increased pregnancy rates in an abortion-prone animal model stress. The results suggested the therapeutic potential of the TIGIT-Fc fusion protein in reinstating immune tolerance in failing pregnancies.
母体免疫-内分泌机制与胎儿机制的完美同步是成功妊娠所必需的。在本报告中，我们检测到了母体-胎儿界面的蜕膜免疫细胞表达 T 细胞免疫受体酪氨酸抑制基序（T cell immunoreceptor with Ig and ITIM domains，TIGIT），它是一种触发免疫耐受的共抑制受体。我们通过连接 TIGIT 的细胞外结构域和沉默的 Fc 片段生成了重组 TIGIT-Fc 融合蛋白。TIGIT-Fc 处理人蜕膜抗原呈递细胞（antigen presenting cells，APCs）、蜕膜树突状细胞（dendritic cells，dDCs）和蜕膜巨噬细胞（macrophages，dMϕs）增加了白细胞介素 10 的产生，并诱导蜕膜 APC 强烈地将蜕膜 CD4 T 细胞向经典 T2 表型极化。我们进一步提出，Notch 信号在蜕膜免疫细胞亚群的转录调控中显示出关键作用。此外，在植入前将 TIGIT-Fc 给予易流产的 CBA/J 怀孕小鼠，诱导 CD4 叉头框 P3（forkhead box P3，Foxp3）调节性 T 细胞和耐受树突状细胞，并增加流产倾向动物模型中的妊娠率。这些结果表明，TIGIT-Fc 融合蛋白在恢复失败妊娠中的免疫耐受方面具有治疗潜力。
