Evolution of non-cytotoxic uterine natural killer cells

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 CD56(bright)CD16(-) 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 CD56(bright)CD16(-) 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.

Figure 1. Biological rhythm of CD56^brightNK cells in the human endometrium and the decidua

uNK cell population cyclically patterns in tandem with the menstrual cycle. With successful implantation, uNK cells further increase in the decidua and dwindle thereafter by the end of second trimester. E2, estradiol; P4, progesterone; LH, leutinizing hormone.

Figure 2. Hormone-cytokine influence on evolution and function of uNK cells

The hormone-cytokine milieu in the endometrium and the decidua can choreograph recruitment, expansion, differentiation and maturation of uNK cells in addition to their potential influence on angiogenesis and cytotoxicity. MIP, macrophage inflammatory protein; CXCR, CX chemokine receptor; CXCL, CX chemokine ligand; TGF, transforming growth factor; SCP, stromal cell protein.

Figure 3. Origin of uNK cells-endometrium and decidua as “inducible tertiary lymphoid tissue”

In the homing pathway, local hormonal milieu can recruit and amplify circulating CD56^brightCD16⁻NK cells. In the tertiary lymphoid pathway the lineage committed-progenitor cells (CD45⁺CD34⁺) and circulating NK cells differentiate into CD56^brightCD16⁻ NK cells in the presence of stromal cells and IL-15. Pregnancy induced hypoxia can trigger translational up-regulation of angiogenic machineries and support pregnancy. Compromised pregnancy compatible intrauterine milieu may allow further maturation into cytotoxic CD56^dimCD16⁺ NK cells causing pregnancy complications. Symbols: angiogenic factors; cytolysis machinery Abbreviations: VEGF C, vascular endothelial growth factor C; PlGF, placenta growth factor; IP 10, interferon gamma inducible protein