Abstract
The maternal decidua is an immunologically complex environment that balances maintenance of immune tolerance to fetal paternal antigens with protection of the fetus against vertical transmission of maternal pathogens. To better understand host immune determinants of congenital infection at the maternal-fetal tissue interface, we performed a comparative analysis of innate and adaptive immune cell subsets in the peripheral blood and decidua of healthy rhesus macaque pregnancies across all trimesters of gestation and determined changes after Zika virus (ZIKV) infection. Using one 28-color and one 18-color polychromatic flow cytometry panel we simultaneously analyzed the frequency, phenotype, activation status and trafficking properties of αβ T, γδ T, iNKT, regulatory T (Treg), NK cells, B lymphocytes, monocytes, macrophages, and dendritic cells (DC). Decidual leukocytes showed a striking enrichment of activated effector memory and tissue-resident memory CD4+ and CD8+ T lymphocytes, CD4+ Tregs, CD56+ NK cells, CD14+CD16+ monocytes, CD206+ tissue-resident macrophages, and a paucity of B lymphocytes when compared to peripheral blood. t-distributed stochastic neighbor embedding (tSNE) revealed unique populations of decidual NK, T, DC and monocyte/macrophage subsets. Principal component analysis showed distinct spatial localization of decidual and circulating leukocytes contributed by NK and CD8+ T lymphocytes, and separation of decidua based on gestational age contributed by memory CD4+ and CD8+ T lymphocytes. Decidua from 10 ZIKV-infected dams obtained 16-56 days post infection at third (n=9) or second (n=1) trimester showed a significant reduction in frequency of activated, CXCR3+, and/or Granzyme B+ memory CD4+ and CD8+ T lymphocytes and γδ T compared to normal decidua. These data suggest that ZIKV induces local immunosuppression with reduced immune recruitment and impaired cytotoxicity. Our study adds to the immune characterization of the maternal-fetal interface in a translational nonhuman primate model of congenital infection and provides novel insight in to putative mechanisms of vertical transmission.
Highlights
Successful maintenance of pregnancy requires a balance between sustaining an immune tolerant state to prevent rejection of foreign paternal-origin fetal antigens and at the same time protect the fetus against vertical transmission of microbial pathogens [1]
To examine immune cell populations at the maternal-fetal interface in normal rhesus macaques, we conducted a crosssectional analysis of first (n=3), second (n=3), and third (n=5) trimester decidua obtained at the time of C-section in healthy pregnancy and compared it with blood obtained from gestationmatched healthy, uninfected dams experiencing normal pregnancies (Table 1)
Peripheral blood mononuclear cells (PBMC) and decidual leukocytes were evaluated with two flow cytometry panels, one 28-color panel focused on adaptive immunity, and one 18-color innate cell focused panel (Supplemental Table 3)
Summary
Successful maintenance of pregnancy requires a balance between sustaining an immune tolerant state to prevent rejection of foreign paternal-origin fetal antigens and at the same time protect the fetus against vertical transmission of microbial pathogens [1]. Studies in the first trimester of pregnancy in humans have shown that NK cells account for 50-90% of the decidual leukocyte population and predominantly have a CD56bright CD16– phenotype [7, 9]. Decidual CD8+ T cells are key players in recognition of foreign antigen and have been shown to contain fetal-specific CD8+ T cells [22,23,24,25]. It is not known whether decidual CD8+ T lymphocytes mount an antigenspecific response against pathogens; one study demonstrating decidual CD8+ T cells binding to EBV-specific tetramers was not conclusive [26, 27]. We are using the rhesus macaque nonhuman primate (NHP) model to study factors predisposing to placental transmission of congenital infections such as cytomegalovirus (CMV) and Zika virus (ZIKV) [28,29,30]
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