Endosomal Signaling and a Novel Pathway Defined by the Natural Killer Receptor KIR2DL4 (CD158d)

In addition to ligand-induced activation of receptors at the cell surface, certain internalized receptor-ligand complexes are activated in endosomes which are, now recognized as important intracellular platforms of signal transduction. The major receptor families that signal from endosomes and illustrate the diversity and complexity of endosomal signaling include receptor tyrosine kinases (RTKs), G-protein-coupled receptors (GPCRs) and toll-like receptors (TLRs). Natural killer (NK) cells, an important component of the innate immune system, not only provide a rapid defense against foreign invaders, such as bacteria and viruses, but also positively shape local responses by cytokine and chemokine secretion. The NK cell receptor KIR2DL4 (CD158d) utilizes a new mode of endosomal signaling after binding its ligand, soluble HLA-G, in the extracellular milieu. Internalization of the receptor and its ligand into endosomes and initiation of signaling at this site result in a proinflammatory and proangiogenic response with important functions at sites of ligand expression, such as at the maternal-fetal interface during early pregnancy. After a brief overview of the modes of endosomal signaling and its value in generating distinct physiological responses, this review will highlight the mechanism and physiological significance of a novel intracellular signaling pathway used by the endosome-resident immune receptor KIR2DL4.