KIR2DL4 (CD158d): An activation receptor for HLA-G

Abstract

KIR2DL4 is an unusual killer cell immunoglobulin-like receptor (KIR) family member in terms of its structure, expression, cellular localization, and signaling properties. The most conserved KIR in evolution, it is referred to as a framework KIR gene and is expressed by all natural killer (NK) cells and a subset of T cells. Although it has a long cytoplasmic tail that is typical of inhibitory KIR, engagement of this receptor results in the activation of NK cells, not for cytotoxicity, but for cytokine and chemokine secretion. Unlike all other KIRs, which are expressed on the surface of NK cells, KIR2DL4 resides in endosomes. It signals from this intracellular site for a proinflammatory and proangiogenic response, using a novel endosomal signaling pathway that involves the serine/threonine kinases DNA-PKcs and Akt. The only known ligand of KIR2DL4 is HLA-G. Soluble HLA-G accumulates in KIR2DL4(+) endosomes. Unlike classical HLA molecules that serve as ligands for other KIR family members, in healthy individuals, HLA-G expression is restricted to the fetal trophoblast cells that invade the maternal decidua during early pregnancy. Since NK cells constitute the predominant lymphocyte subset at this site, the proinflammatory/proangiogenic outcome of the interaction between KIR2DL4 and soluble HLA-G supports a role for KIR2DL4 in the extensive remodeling of the maternal vasculature during the early weeks of pregnancy.

Keywords: HLA-G; KIR; NK; pregnancy.

FIGURE 1

Overview of the KIR family of inhibitory (red) and activating (green) NK cell receptors. They bind MHC-I molecules and are located on the cell surface, with the exception of KIR2DL4, which is present in endosomes. The activating receptors interact with the adapters DAP12 or FcRγ via charge-based interactions in the transmembrane region. The KIR2DL/3DL receptors (except KIR2DL4) use ITIM-based inhibitory signaling pathways to block NK effector functions, while KIR2DS/3DS receptors activate NK cells via ITAM-based pathways. In contrast, KIR2DL4 signals from endosomes for a unique secretory response, but does not activate cytotoxicity.

FIGURE 2

A potential role for KIR2DL4–HLA-G interactions in early pregnancy. NK cells are abundant in the non-pregnant endometrium (left panel) in the secretory phase of the menstrual cycle. In early pregnancy (right panel), interactions between fetal extravillous trophoblast cells (EVT) and NK cells in the decidua contribute to the remodeling of the spiral arteries to allow increased blood supply to the fetus. Fetal trophoblast cells secrete soluble HLA-G (sG), which can be endocytosed by KIR2DL4 into endosomes. Endosomal signaling then results in a sustained proinflammatory/proangiogenic secretory response that may promote the vascular changes seen in early pregnancy.