REVIEW ARTICLE: Evolution of Non‐Cytotoxic Uterine Natural Killer Cells

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Abstract
The immune tolerance and de novo vascularization are two highly intriguing processes at the maternal–fetal interface that appear to be central to normal pregnancy outcome. Immune tolerance occurs despite the local presence of an active maternal immune system including macrophages, dendritic cells and specialized CD56brightCD16− uterine natural killer (uNK) cells (65–70%). Recent observations indicate that the phenotypic and functional repertoire of uNK cells is distinct from peripheral blood NK and endometrial NK cells, challenging the understanding of their temporal occurrence and function. Origin and specialized programming of uNK cells continue to be debated. uNK cells, replete with an armamentarium to kill the foreign, tolerate the conceptus and facilitate pregnancy. Why do these uNK cells remain non‐cytotoxic? Are these NK cells ‘multitasking’ in nature harboring beneficial and detrimental roles in pregnancy? Are there distinct subpopulations of NK cells that may populate the decidua? We propose that the endometrium/decidua functions as an ‘inducible tertiary lymphoid tissue’ that supports the recruitment and expansion of CD56brightCD16− NK cells and induces transcriptional up‐regulation of angiogenic machinery in response to exposure to local hormonal factors, cytokine milieu and perhaps hypoxia. The angiogenic features of uNK cells could further result in a ‘multitasking’ phenotype that still remains to be characterized. This article discusses the factors and pathways that bridge the angiogenic and non‐cytotoxic response machineries at the maternal–fetal interface.