Deletion of fetal-specific maternal CD4+ T cells during human pregnancy

Abstract

Abstract Maternal T cell responses to fetal alloantigens are thought to play a critical role in facilitating successful pregnancy, but mechanisms of maternal-fetal tolerance remain largely unclear. Studies in murine models suggest that deletion of fetus-specific CD4+ T cells may contribute to tolerance; however, the role of deletion in human pregnancy is unknown. Here we use bulk TCR sequencing to assess changes in the maternal CD4+ T cell repertoire over the course of human pregnancy. Peripheral blood was collected from four primigravid women during the first and third trimesters, and a single peripheral blood sample was taken from their respective partners. Maternal CD4+ T cells were isolated using FACS, and TCR sequencing was performed on genomic DNA using the ImmunoSeqTM assay. The maternal alloreactive repertoire was defined using mixed lymphocyte reactions (MLRs) in which irradiated paternal PBMCs were used to stimulate maternal blood. An average of 32,077 (SD=9,609) unique CD4+ T cell clones/subject were identified at each timepoint. Within the small cohort examined in this study, we observed a notable increase in repertoire clonality in two of four women (average change in clonality=0.0045 vs. 0.0003). The two subjects that had an increase in CD4 clonality had a significant reduction in the number of alloreactive CD4 clones detected in the third trimester relative to the first whereas this number was effectively unchanged in the other two subjects (first:third=1:0.1±0.02 vs. 1:1.0±0.1). These findings suggest that substantial deletion of CD4+ alloreactive clones occurs in some women over the course of gestation. Deletion of alloreactive T cell clones may thus represent one mechanism of maternal-fetal tolerance in human pregnancy.