Analysis of TCR Repertoire and PD-1 Expression in Decidual and Peripheral CD8+T Cells Reveals Distinct Immune Mechanisms in Miscarriage and Preeclampsia

CD8(+)T cells, the most abundant T cell subset in the decidua, play a critical role in the maintenance of pregnancy. The majority of decidual CD8(+)T cells have an effector memory phenotype, while those in the peripheral blood display a naive phenotype. An increased amount of highly differentiated CD8(+)T cells in the decidua indicates local antigen stimulation and expansion, albeit these CD8(+)T cells are suppressed. In decidual CD8(+)T cells, co-inhibitory molecules such as PD-1, TIM-3, LAG-3, and CTLA-4 are upregulated, reflecting the suppression of cytotoxicity. Previous studies established the importance of the PD-1/PD-L1 interaction for feto-maternal tolerance. CD8(+)T cells could directly recognize fetal-specific antigens, such as HLA-C, expressed by trophoblasts. However, although fetal-specific CD8(+)T cells have been reported, their TCR repertoires have not been identified. In this study, we analyzed the TCR repertoires of effector memory CD8(+)T cells (CD8(+)EM cells) and naive CD8(+)T cells (CD8(+)N cells) in the decidua and peripheral blood of women with normal or complicated pregnancy and examined PD-1 expression at a single-cell level to verify whether antigen-specific CD8(+)T cells accumulate in the decidua and to identify immunological differences related to the suppression of antigen-specific CD8(+)T cells between normal pregnancy, miscarriage, and preeclampsia. We observed that some TCR beta repertoires, which might recognize fetal or placental antigens, were clonally expanded. The population size of clonally expanded CD8(+)EM cells was higher in the decidua than in the peripheral blood. CD8(+)EM cells began to express PD-1 during the course of normal pregnancy. We found that the total proportion of decidual CD8(+)EM cells not expressing PD-1 was increased both in miscarriage and in preeclampsia cases, although a different mechanism was responsible for this increase. The amount of cytotoxic CD8(+)EM cells increased in cases of miscarriage, whereas the expression of PD-1 in clonally expanded CD8(+)EM cells was downregulated in preeclampsia cases. These results demonstrated that decidual CD8(+)EM cells were able to recognize fetal-specific antigens at the feto-maternal interface and could easily induce fetal rejection.