Characterization of migration of natural killer cells to the uterus during pregnancy

Natural Killer (NK) lymphocytes accumulate in the uterus during decidualization and early pregnancy. They have crucial roles in uterine artery modification. Uterine (u) NK cell precursors (pre-uNK) do not self-renew in the uterus, and spleen is the only identified source enriched by pregnancy. This thesis tested the hypothesis that pre-uNK cells migrate from other lymphoid tissues to the uterus. Adoptive cell transfers to NK-/uNK - mice. Peripheral lymph nodes (PLN) were an important source of pre-uNK cells but all tissues tested except pelvic LN draining the pregnant the uterus had transplantable pre-uNK cells. To address the regulatory molecules involved in NK cell homing to uterus, implantation sites were studied in mice that were genetically disrupted for L-selectin, chemokine receptors (CCR2 and CCR5), or CC-chemokine (MIP-1alpha). These mutant mice showed no abnormalities in uNK cell frequencies or localization. Mice deficient in lymphotoxin (LT)alpha or LTbeta receptor showed only a delay in the development of the decidua basalis (DB). Circulating pre-uNK cells must interact with endothelium to egress into uterus. To determine pregnancy effects on uterine endothelial cell adhesiveness for lymphocytes, human peripheral blood lymphocytes (PBL), pre-labeled with CD56, a human uNK cell marker, were used as indicator cells in frozen tissue section adhesion assays. More CD56+ cells bound to uterine sections harvested from pregnant compared to virgin mice. If uteri were decidualized, PBL adhered as clusters rather than single cells, and were restricted to the DB rather than randomly distributed. Adhesion was L-selectin and alpha4 integrin-dependent. Pregnancy also induced increased L-selectin and alpha4 integrin-dependent adhesion in selected peripheral tissues. Further, pregnancy modified lymphocytes themselves because adhesion of splenocytes from pregnant versus virgin donors was greater on the HEV of the PLN from virgin mice. To address steroid hormone contribution to the dynamic gains in lymphocyte-endothelial interaction, ovariectomized mice were studied. Hormone replacement therapy using 17beta-estradiol and/or progesterone induced greater adhesiveness in uterine endothelial cells, PLN and Peyer's patches. Hormone-induced and pregnancy-mediated effects were quantitatively similar. Thus, pre-NK cell migration to uterus depends on coordinated ovarian hormone actions on both lymphocytes and specialized endothelia.