HLA-G-mediated NK cell senescence promotes vascular remodeling: implications for reproduction

Abstract

The uterus in early pregnancy is a non-lymphoid organ that is enriched in natural killer (NK) cells. Studies to address the role of these abundant human NK cells at the maternal/fetal interface have focused on their response to the major histocompatibility complex (MHC) molecules on fetal trophoblast cells that they contact. The interaction of maternal NK cell receptors belonging to the killer cell immunoglobulin-like receptor (KIR) family with trophoblast MHC class I molecules in pregnancy can regulate NK cell activation for secretion of pro-angiogenic factors that promote placental development. This review will cover the role of KIR at the maternal/fetal interface and focus on KIR2DL4, a KIR family member that is uniquely poised to play a role in pregnancy due to the restricted expression of its ligand, human leukocyte antigen (HLA)-G, by fetal trophoblast cells early in pregnancy. The pathways by which KIR2DL4-HLA-G interactions induce the cellular senescence of NK cells and the role of the resulting senescence-associated secretory phenotype (SASP) in vascular remodeling will be discussed in the context of reproduction.

Figure 1

KIR2DL4–HLA-G interactions: relevance to pregnancy. The non-pregnant endometrium (left panel) contains an abundance of NK cells in the secretory phase of the menstrual cycle. Interactions between fetal EVT cells and decidual NK cells cooperate to remodel the spiral arteries that promote increased blood supply to the fetus. Soluble HLA-G secreted by fetal trophoblast cells can be endocytosed into KIR2DL4-containing endosomes. Endosomal signaling leads to the cellular senescence of NK cells and a sustained secretory response termed the SASP. This SASP would remodel the local environment to promote vascularization required for a growing fetus. EVT, extravillous trophoblast; HLA, human leukocyte antigen; KIR, killer cell immunoglobulin-like receptor; NK, natural killer; SASP, senescence-associated secretory profile; uPAR, urokinase plasminogen activator receptor.