The Roles And Mechanisms Of The Immune Microenvironment In Maternal-fetal Interface Contributing To Parturition And Preterm Labor

Preterm birth is the leading cause of neonatal morbidity and mortality.The mechanisms underlying the initiation of human parturition remain poorly understood,bringing the difficulties in preventing and treating spontaneous prematurity in clinic.The decidua parietalis and basalis compose the maternal-fetal interface,which plays a vital function in pregnancy and parturition,including coordinating the immune tolerance to the fetus,a semi-allograft for the maternal immune system and its turbulence usually causing preterm.Although it is well known that T lymphocytes are the crucial components of the immune tolerance,the patterns of distribution,the functions and regulation of subgroups of decidual T lymphocytes in term labor and preterm labor are yet to be discovered.Considering that T lymphocytes are highly heterogeneous,the single-cell transcriptomics sequencing,which identifies information at single-cell level,was employed in this study.The signals to parturition come from both maternal and fetal origin,so they might have effects on T cell differentiation,especially into Treg or Th17 cells,the balance between which plays an important role in maternal-fetal immune tolerance.This article discovers the patterns of distribution and features of different subtypes of T lymphocytes in maternal-fetal interface in late pregnancy using single-cell RNA sequencing.Using selected maternal or fetal factors,we found that ORM1 may play a significant role in parturition by suppressing the differentiation of Treg cells.Results:A)The patterns of distribution and features of different subtypes of T lymphocytes in maternal-fetal interfaceSingle-cell RNA sequencing was performed using T lymphocytes isolated from the maternal-fetal interface?basal decidua,parietal decidua?tissues in the preterm and term labor pregnant women.According to the correlation analysis of their gene expression profiles,four T lymphocyte subsets,i.e.,CCR7^highTCF7^highHLA-DPA1^low Na?ve-type cells,IL2RA^highTIGIT^highCTLA4^highFOXP3^highTreg-type cells,MKI67^highCDK1^highhigh prolife-ration activity T cells,and NKG7^highGZMA^highIFNG^high cytotoxic-type T cells,were found to be conservative within two batches of decidual samples being sequenced.These clusters of T cells have a strong correlation with preterm birth,and their distribution in decidua manifested significant differences between preterm and term delivery.In the IL2RA^highTIGIT^highCTLA4^highFOXP3^high Treg cells,it was found that the genes such as CTLA4 and IL2RB were significantly up-regulated in the preterm group,whereas the inhibitory transcriptional factors TIGIT and IL2RA were down-regulated.In NKG7^highGZMA^highIFNG^high T cells,GZMA and CD74 were significantly up-regulated in the preterm group,while LYST showed a down-regulation trend.B)Distribution and regulation of maternal-fetal interface Treg cellsFurtherly,we verified that the proportion of Treg in CD4⁺T cells was significantly decreased in the parietal decidua of premature birth,and we also found that the ratio of Treg to CD4⁺T cells at the maternal-fetal interface was significantly higher in the SRC1/SRC2double-KO mice which manifested significantly delayed parturition compared with WT mice.Moreover,we found that serum amyloid A-1 protein?ORM1?,which was recently found to be up-regulated in the serum of preterm labor patients by our team,can significantly induce the apoptosis of Treg cells as well as inhibit the differentiation of Treg from na?ve cells.C)Possible mechanism underlying the contribution of Treg lymphocyte to initiation of laborTreg cells can not directly enhance or reduce the contractility of uterine smooth muscles.It may exert their regulatory effects on uterine myometrium indirectly by regulating other cell subgroups functions.Conclusion:The distribution differences of specific T cell subsets in decidua between PTL and TIL may play pivotal roles in human parturition and contribute to the occurrence of preterm labor.ORM1 may play a significant role in parturition by suppressing the differentiation of Treg.The interventions of specific subsets of T cells or its regulators may provide new strategies and hope for the treatment of preterm birth.