Gestationally driven trafficking of decidual lymphocytes assessed by serial intravascular staining

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The decidua is a specially modified mucosa that harbors a unique composition of leukocytes. Despite the importance of maternal-fetoplacental immune interactions during pregnancy, the gestationally-driven population dynamics of decidual leukocytes has been difficult to ascertain, and the transition from the menstrual cycle to early pregnancy is not readily studied in human pregnancy. Disturbance of the mechanisms that regulate population maintenance and trafficking of decidual leukocytes at the maternal-fetal interface is thought to underlie morbidity and mortality in pregnancy (i.e., preeclampsia, preterm labor, fetal growth restriction) and presents a powerful diagnostic and therapeutic target. Thus, this R21 Exploratory/Developmental Grant application aims to establish a novel pregnant macaque model defining trafficking of peripheral blood cells to the decidua using the novel technique of serial intravascular staining (SIVS) with the following Specific Aims. Specific Aim 1: To determine the trafficking and population dynamics of decidual lymphocytes, including decidual NK cells, in pregnant rhesus monkeys. We will test the hypothesis that trafficking from the peripheral blood and proliferation and apoptosis of tissue-resident decidual lymphocytes drive population dynamics across pregnancy. Further, the distribution of these lymphocytes with respect to the decidual vasculature will provide insight into their function and mechanisms of trafficking. Specific Aim 2. To determine the trafficking of peripheral blood lymphocytes, including NK cells, to the nonpregnant endometrium. We will test the hypothesis that the trafficking of lymphocytes to the developing maternal-fetal interface is initiated in the late luteal phase of the menstrual cycle, independent of the presence of an embryo or developing placenta. Our proposed studies will answer the following fundamental questions: Which lymphocytes actively traffic between systemic vasculature and decidual residency during pregnancy? What is the balance of cell proliferation and cell death of decidua-resident lymphocytes across gestation? What is the distribution of trafficking and resident lymphocytes relative to the vasculature within the decidua? And, is trafficking from the blood to the uterus initiated in the luteal phase in preparation for the establishment of pregnancy? Determining the origin and dynamics of decidual lymphocytes is necessary to advance the hypothesis of their pivotal role in hemochorial placentation into clinically actionable intelligence. The R21 Exploratory/Developmental Grant mechanism supports research projects in their early and conceptual stages. The application of the SIVS paradigm to the pregnant nonhuman primate model could have a major impact on our understanding of the reproductive immunology of the maternal-fetal interface. Furthermore, these methodologies for assessing trafficking of immune cells in vivo in the nonhuman primate model will be powerful tools to apply to other experimental settings, including infectious disease in pregnancy and hematopoietic stem cell and solid organ transplantation.