The Multiple Faces of the Decidual Natural Killer Cell

Abstract

The decidual NK (dNK) cell is called on to support placental growth by providing an array of growth factors that directly transform the spiral artery and direct trophoblast invasion. Successful transformation is dependent upon adequate stimulation paradoxically stimulating the cell for placental support rather than cytotoxicity. With the identification of its supportive role, the presence of an intact cytotoxic mechanism has been confusing. Investigators have found that the cell remains fully capable of cytotoxic responses particularly in response to pathogen-specific signals. We postulate a dual threshold model where moderate stimulation results in release of stimulatory factors supporting placentation while intense stimulation, particularly triggered through pathogen-specific receptors, restores the cell to its protective, cytotoxic, role. Individual dNK cells mature attaining the capacity to respond to the delivery of cognate signals. The process, known as 'licensing' tunes responsiveness to the degree to which stochastically selected inhibitory receptors block cytotoxic response to self. A changing licensing milieu within the decidua may result in altered and unsuitable receptor expression. We postulate that a heterogeneous population of dNK cells where cells inappropriately licensed for the milieu contributes to pathology.

The Galectin-9/Tim-3 pathway is involved in the regulation of NK cell function at the maternal–fetal interface in early pregnancy

“…pNK cells are mainly responsible for fighting pathogen infections via secretion of perforin and granzymes, but dNK cells participate in fetomaternal immune tolerance, trophoblast invasion and vascular remodeling through secretion of various types of cytokines. 15,36 The environment at the maternal-fetal interface is assumed to modify recruited pNK cells, instructing them to be dNK-like cells in phenotype and function. 28,37 Here, we found that the coculture of pNK cells with trophoblasts significantly increased Th2-type cytokine production and decreased Th1-type cytokine and perforin expression by pNK cells.…”

Maternal and Fetal Factors that Contribute to the Localization of T Regulatory Cells During Pregnancy

“…Recent evidence has suggested that Tregs can directly control NK cell activity 19 . Since uterine NK cells are phenotypically distinct from those found in the periphery, it is not clear if those findings are applicable 20 . It is clear that uterine NK cells are necessary to support pregnancy, but retain the potential to cause pathology 20 .…”

“…19 As uterine NK cells are phenotypically distinct from those found in the periphery, it is not clear if those findings are applicable. 20 It is clear that uterine NK cells are necessary to support pregnancy, but retain the potential to cause pathology. 20 Perhaps local Tregs modulate NK cell activity to favor a permissive environment for pregnancy.…”

TIM-3: a crucial regulator of NK cells in pregnancy

“…1 As the predominant innate immune cells during gestation, natural killer (NK) cells have been proven to mediate the establishment of maternal-fetal immune tolerance and to initiate appropriate defenses against infections. 2 Tim-3, a member of the T-cell immunoglobulin and mucin domain proteins, has emerged as a key molecule in both innate and adaptive responses and represents a promising novel therapeutic target. 3,4 The expression of Tim-3 has been shown to associate with the maturation or activation of NK cells, and the surrounding immune microenvironment of NK cells also exerts some influence on Tim-3 expression.…”