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Introduction: In pregnancy, the mother and fetus differ in HLA antigens, and yet the maternal immune system generally tolerates the fetus. KIR receptors expressed by maternal uterine NK cells at the maternal-fetal interface directly interact with HLA-C on extravillous trophoblast cells for optimal placental development. In this study, we aimed to determine whether there is a preferential selection for HLA compatibility and specific KIR/HLA-C combinations in uncomplicated and preeclamptic naturally conceived pregnancies compared to what would be expected by chance., Methods: Genotyping for maternal and fetal HLA-A, -B, -C, -DR, and -DQ, and maternal KIR was performed for 451 uncomplicated pregnancies and 77 pregnancies complicated with preeclampsia. The number of HLA antigen (mis)matches between mother and fetus was calculated and compared to expected values obtained by randomization of the HLA haplotype, inherited from the father, over the existing maternal haplotype of the fetuses. A similar methodology was executed for analysis of the KIR/HLA-C data (n=309)., Results: In uncomplicated pregnancies, the degree of maternal-fetal HLA matching was not different than expected-by-chance values. In preeclamptic pregnancies, the degree of maternal-fetal HLA matching was different in observed compared to expected-by-chance values (p=0.012). More specifically, the degree of maternal-fetal matching of HLA-C was higher in the actual preeclamptic pregnancies than was expected-by-chance (p=0.007). Preeclamptic pregnancies showed an overall tendency towards higher maternal-fetal HLA compatibility, for total HLA matches (p=0.021), HLA class I (p=0.038) and HLA-C (p=0.025) compared to uncomplicated pregnancies., Conclusion: The data suggest that there is no preferential selection of maternal-fetal HLA compatibility in uncomplicated pregnancies. In contrast, increased total HLA, HLA class I and, especially, HLA-C compatibility is associated with preeclampsia, suggestive for a role of HLA mismatches in immune regulation leading to uncomplicated pregnancy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 van ‘t Hof, Schotvanger, Haasnoot, van der Keur, Roelen, Lashley, Claas, Eikmans and van der Hoorn.)

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 TCRβ 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., (Copyright © 2020 Morita, Tsuda, Kobayashi, Hamana, Tsuda, Shima, Nakashima, Ushijima, Kishi and Saito.)