RESEARCH ARTICLE Interleukin-11 Signaling Is Required for the Differentiation of Natural Killer Cells at the Maternal–Fetal Interface

Interleukin-11 (IL-11) is a multifunctional hematopoietic growth factor that has been implicated in the control of reproduction. Studies on IL-11 receptor- (IL-11R)-deficient mice showed that female mice are infertile due to defective decidualization. In this report, we evaluated the development of decidual cells, immune cells, and the vasculature associated with the implantation site of IL-11R–deficient mice; with the aim of better understanding the nature of the fertility defect. Messenger RNAs for decidual differentiation, such as decidual prolactin-related protein and prolactin-like protein-J are expressed in the IL-11R mutant. However, the number of decidual cells expressing these genes is decreased in the mutant compared with the wild-type control. Although, trophoblast cells differentiate and express placental lactogen-I in the IL-11R–deficient uterine environment, they fail to progress and expand in number. Defects in the organization of the decidual vasculature were also apparent in the IL-11Rmutant uterus. The most dramatic effect of IL-11 signaling was on the hematopoietic environment of the uterine decidua. Differentiated/ perforin-expressing uterine natural killer (NK) cells were virtually absent from implantation sites of IL-11R mutant mice. NK cell precursors were capable of homing to the IL-11R–deficient uterus and a known regulator of NK cell differentiation; IL-15 was expressed in the IL-11R mutant uterus. Splenic NK cells from IL-11R mutant mice were also able to respond to IL-15 in vitro. Thus, the defect in NK precursor cell maturation was not intrinsic to the NK precursor cells but was dependent upon the tissue environment. In summary, IL-11 signaling is required fo