Uterine Natural Killer Cells: Functional Distinctions and Influence on Pregnancy in Humans and Mice.

Our understanding of development and function of natural killer (NK) cells has progressed significantly in recent years. However, exactly how uterine NK (uNK) cells develop and function is still unclear. To help investigators that are beginning to study tissue NK cells, we summarize in this review our current knowledge of the development and function of uNK cells, and what is yet to be elucidated. We compare and contrast the biology of human and mouse uNK cells in the broader context of the biology of innate lymphoid cells and with reference to peripheral NK cells. We also review how uNK cells may regulate trophoblast invasion and uterine spiral arterial remodeling in human and murine pregnancy.

The Residual Innate Lymphoid Cells in NFIL3-Deficient Mice Support Suboptimal Maternal Adaptations to Pregnancy.

Uterine NK cells are innate lymphoid cells (ILC) that populate the uterus and expand during pregnancy, regulating placental development and fetal growth in humans and mice. We have recently characterized the composition of uterine ILCs (uILCs), some of which require the transcription factor NFIL3, but the extent to which NFIL3-dependent cells support successful reproduction in mice is unknown. By mating Nfil3 (-/-) females with wild-type males, here we show the effects of NFIL3 deficiency in maternal cells on both the changes in uILCs during pregnancy and the downstream consequences on reproduction. Despite the presence of CD49a(+)Eomes(-) uILC1s and the considerable expansion of residual CD49a(+)Eomes(+) tissue-resident NK cells and uILC3s in pregnant Nfil3 (-/-) mice, we found incomplete remodeling of uterine arteries and decidua, placental defects, and fetal growth restriction in litters of normal size. These results show that maternal NFIL3 mediates non-redundant functions in mouse reproduction.

Assessment of Maternal Vascular Remodeling During Pregnancy in the Mouse Uterus.

The placenta mediates the exchange of factors such as gases and nutrients between mother and fetus and has specific demands for supply of blood from the maternal circulation. The maternal uterine vasculature needs to adapt to this temporary demand and the success of this arterial remodeling process has implications for fetal growth. Cells of the maternal immune system, especially natural killer (NK) cells, play a critical role in this process. Here we describe a method to assess the degree of remodeling of maternal spiral arteries during mouse pregnancy. Hematoxylin and eosin-stained tissue sections are scanned and the size of the vessels analysed. As a complementary validation method, we also present a qualitative assessment for the success of the remodeling process by immunohistochemical detection of smooth muscle actin (SMA), which normally disappears from within the arterial vascular media at mid-gestation. Together, these methods enable determination of an important parameter of the pregnancy phenotype. These results can be combined with other endpoints of mouse pregnancy to provide insight into the mechanisms underlying pregnancy-related complications.

Composition, Development, and Function of Uterine Innate Lymphoid Cells.

Innate lymphoid cells (ILCs), including NK cells, contribute to barrier immunity and tissue homeostasis. In addition to the role of uterine NK cells in placentation and fetal growth, other uterine ILCs (uILCs) are likely to play roles in uterine physiology and pathology. In this article, we report on the composition of uILCs in the endometrium during the luteal phase and in the decidua during early pregnancy. Whereas nonkiller uILC1s and uILC2s are barely detectable in mouse and not detected in humans, a sizeable population of uILC3s is found in human endometrium and decidua, which are mostly NCR(+) and partially overlap with previously described IL-22-producing uterine NK cells. Development of mouse uILC3 is Nfil3 independent, suggesting unique features of uILCs. Indeed, although the cytokine production profile of mouse uILCs recapitulates that described in other tissues, IL-5, IL-17, and IL-22 are constitutively produced by uILC2s and uILC3s. This study lays the foundation to understand how ILCs function in the specialized uterine mucosa, both in tissue homeostasis and barrier immunity and during pregnancy.

MHC-dependent inhibition of uterine NK cells impedes fetal growth and decidual vascular remodelling.

NK cells express variable receptors that engage polymorphic MHC class I molecules and regulate their function. Maternal NK cells accumulate at the maternal-fetal interface and can interact with MHC class I molecules from both parents. The relative contribution of the two sets of parental MHC molecules to uterine NK cell function is unknown. Here we show that, in mice, maternal and not paternal MHC educates uterine NK cells to mature and acquire functional competence. The presence of an additional MHC allele that binds more inhibitory than activating NK cell receptors results in suppressed NK cell function, compromised uterine arterial remodelling and reduced fetal growth. Notably, reduced fetal growth occurs irrespectively of the parental origin of the inhibitory MHC. This provides biological evidence for the impact of MHC-dependent NK inhibition as a risk factor for human pregnancy-related complications associated with impaired arterial remodelling.

Gamma activity and reactivity in human thalamic local field potentials.

Depth recordings in patients with Parkinson's disease on dopaminergic therapy have revealed a tendency for oscillatory activity in the basal ganglia that is sharply tuned to frequencies of approximately 70 Hz and increases with voluntary movement. It is unclear whether this activity is essentially physiological and whether it might be involved in arousal processes. Here we demonstrate an oscillatory activity with similar spectral characteristics and motor reactivity in the human thalamus. Depth signals were recorded in 29 patients in whom the ventral intermediate or centromedian nucleus were surgically targeted for deep brain stimulation. Thirteen patients with four different pathologies showed sharply tuned activity centred at approximately 70 Hz in spectra of thalamic local field potential (LFP) recordings. This activity was modulated by movement and, critically, varied over the sleep-wake cycle, being suppressed during slow wave sleep and re-emergent during rapid eye movement sleep, which physiologically bears strong similarities with the waking state. It was enhanced by startle-eliciting stimuli, also consistent with modulation by arousal state. The link between this pattern of thalamic activity and that of similar frequency in the basal ganglia was strengthened by the finding that fast thalamic oscillations were lost in untreated parkinsonian patients, paralleling the behaviour of this activity in the basal ganglia. Furthermore, there was sharply tuned coherence between thalamic and pallidal LFP activity at approximately 70 Hz in eight out of the 11 patients in whom globus pallidus and thalamus were simultaneously implanted. Subcortical oscillatory activity at approximately 70 Hz may be involved in movement and arousal.

Oscillatory activity in the pedunculopontine area of patients with Parkinson's disease.

The pedunculopontine nucleus (PPN) has recently been introduced as a new therapeutic target for deep brain stimulation (DBS) in patients suffering from Parkinson's disease (PD). In a recent case report it was demonstrated that alpha frequency oscillations appear in PPN after the administration of levodopa in PD, indicating a possible physiological role of these oscillations. Here we confirm this result and investigate the functional connectivity and reactivity of subcortical alpha activity by recording LFP activity from the PPN area and EEG in six patients with PD while at rest and in four of them while they performed ipsi- and contralateral self-paced joystick movements. Levodopa strongly promoted 7-11 Hz oscillatory synchronization in the region of PPN and coupling of this activity with similar activity in the cortical EEG. Such coupling was bidirectional. Moreover, the 7-11 Hz oscillatory synchronization in the PPN area increased about 3 s prior to self-paced movements, but only following levodopa treatment. These findings suggest that alpha oscillations in the PPN area may represent a physiological pattern of activity. The subcortical oscillations are coupled to cortical alpha activity and possibly allied to motor related attentional processes.