Homing receptor expression is deviated on CD56+ blood lymphocytes during pregnancy in Type 1 diabetic women.

Type 1 Diabetes Mellitus (T1DM) is characterized by an augmented pro-inflammatory immune state. This contributes to the increased risk for gestational complications observed in T1DM mothers. In normal pregnancies, critical immunological changes occur, including the massive recruitment of lymphocytes, particularly CD56bright NK cells, into early decidua basalis and a 2nd trimester shift towards Type 2 immunity. Decidual CD56bright NK cells arise at least partly from circulating progenitors expressing adhesion molecules SELL and ITGA4 and the chemokine receptors CXCR3 and CXCR4. In vitro studies show that T1DM reduces interactions between blood CD56+ NK cells and decidual endothelial cells by reducing SELL and ITGA4-based interactions. To address the mechanisms by which specific lymphocyte subsets may be recruited from the circulation during pregnancy and whether these mechanisms are altered in T1DM, flow cytometry was used to examine eight peripheral blood lymphocyte subsets (Type 1 (IL18R1+) and Type 2 (IL1RL1+) CD56bright NK, CD56dim NK, NKT and T cells) from control and T1DM women. Blood was collected serially over pregnancy and postpartum, and lymphocytes were compared for expression of homing receptors SELL, ITGA4, CXCR3, and CXCR4. The decline of Type 1/Type 2 immune cells in normal pregnancy was driven by an increase in Type 2 cells that did not occur in T1DM. CD56bright NK cells from control women had the highest expression of all four receptors with greatest expression in 2nd trimester. At this time, these receptors were expressed at very low levels by CD56bright NK cells from TIDM patients. Type 1/Type 2 NKT cell ratios were not influenced by either pregnancy or TIDM. Our results suggest that T1DM alters immunological balances during pregnancy with its greatest impact on CD56bright NK cells. This implicates CD56bright NK cells in diabetic pregnancy complications.

Heterogeneity in composition of mouse uterine natural killer cell granules.

uNK cells differ from cNK cells, as they produce angiogenic molecules critical for normal implantation site development. We evaluated heterogeneity among DBA(+)uNK cells for Prf, Gzma, and Vegfa. Ctsd and Srgn expression was used to assign intracellular sorting of these molecules on gd7, -9, and -14. Vegfa was present in small, granule-free DBA(+)uNK cells at gd7 and in large, granule-rich DBA(+)uNK cells at gd9 and -14. Prf and Gzma were only found in granulated DBA(+)uNK cells (gd9 and -14). All granule-rich Prf(+)DBA(+)uNK cells appeared to coexpress Vegfa. Thus, all DBA(+)uNK cells were Vegfa-producing cells. PC analysis and immunogold ultrastructure confirmed colocalization of Prf/Ctsd in secretory-lysosome granules (PC>0.5). Surprisingly, Gzma and Prf(+)Ctsd(+) were not colocalized (PC<0.5). Rather, Gzma colocalized with Srgn (PC>0.5) in small granules in cells with Vegfa expression (PC<0.5). NK1.1(+)sNK cells and DBA(+)uNK cells expressed genes regulating vesicular traffic (rab11, rab27a, snap23, vamp7), but uNK cells also expressed rab34 and vamp8, molecules associated with constitutive secretion. SEE activated the regulated secretory pathway of DBA(+)uNK cells in vivo, mobilizing Prf and Gzma but not Vegfa. Thus, DBA(+)uNK cells display constitutive and regulated secretion. Further, these results demonstrate that granule-free DBA(+)uNK cells are not quiescent immature cells, but they are cells with potentially significant angiogenic roles before and in addition to their initiation of spiral arterial remodeling.