DataSheet_1_TIGIT-Fc as a Potential Therapeutic Agent for Fetomaternal Tolerance.pdf

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 TH2 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.

成功妊娠的必要条件是母体免疫内分泌机制与胎儿对应机制实现完美同步。本研究在母胎界面的蜕膜免疫细胞中，检测到了表达TIGIT（T cell immunoreceptor with Ig and ITIM domains，即含Ig与ITIM结构域的T细胞免疫受体）的细胞，该分子是一类可触发免疫耐受的共抑制受体。我们通过将TIGIT的胞外域与沉默型Fc片段相连，构建了重组TIGIT-Fc融合蛋白。将TIGIT-Fc作用于人蜕膜抗原呈递细胞（APCs）、蜕膜树突状细胞（dDCs）及蜕膜巨噬细胞（dMϕs）后，可促进白细胞介素10的产生，并诱导蜕膜抗原呈递细胞强力将蜕膜CD4+T细胞极化为典型的TH2表型。我们进一步提出，Notch信号通路在蜕膜免疫细胞亚群的转录调控中发挥关键作用。此外，在着床前期向CBA/J易流产孕鼠体内给予TIGIT-Fc，可诱导CD4+叉头框P3+（Foxp3+）调节性T细胞与耐受型树突状细胞的生成，并提升该应激易流产动物模型的妊娠成功率。研究结果表明，TIGIT-Fc融合蛋白在恢复不良妊娠的免疫耐受方面具备治疗潜力。