Although the fetus is a semi-graft expressing paternal antigens, it is not rejected by the mother because of the feto-maternal tolerance. Epidemiological studies suggest that the risk of developing preeclampsia (PE) is higher in cases with inadequate exposure to paternal antigens (first-time mothers, pregnancies with artificial reproductive technology, oocyte donation, etc.).
Maternal cytotoxic T cells (CTLs) recognize fetal antigens at the T cell receptor (TCR), whereas regulatory T cells (Treg) suppress them. To investigate the role of antigen-specific Tregs and CTLs in human pregnancy, we analyzed the TCR repertoire (clonal variations with specific TCR sequences) from single T cells obtained from the endometrium during pregnancy. In normal pregnancies, the clonally expanded Tregs increased in the late gestation of pregnancies, and "clonal Tregs" were presumed to be paternal antigen-specific Tregs. In normal pregnancies, antigen-specific CTLs are increased, but the expression of PD-1, an inhibitory co-stimulatory molecule, is also elevated. In PE, however, PD-1 expression in clonally expanded CTLs and the number of clonally expanded Tregs were decreased. This suggests that inadequate induction of antigen-specific Tregs and inadequate suppression of antigen-specific CTLs are involved in PE.
Next, to comprehensive search for pathogenesis-related molecules, we performed a single-cell transcriptome and TCR analysis of uterine T cells. The results of this and the prospects for immunological approaches to PE treatment will also be discussed.