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Mini Review ARTICLE

Front. Immunol., 20 August 2012 |

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

  • Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases/National Institutes of Health, Rockville, MD, USA

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: NK, KIR, HLA-G, pregnancy

Citation: Rajagopalan S and Long EO (2012) KIR2DL4 (CD158d): an activation receptor for HLA-G. Front. Immun. 3:258. doi: 10.3389/fimmu.2012.00258

Received: 09 June 2012; Paper pending published: 22 June 2012;
Accepted: 01 August 2012; Published online: 20 August 2012.

Edited by:

Jeroen Van Bergen, Leiden University Medical Center, Netherlands

Reviewed by:

Clair Gardiner, Trinity College Dublin, Ireland
Daniela Pende, Istituto di Ricovero e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria San Martino – Istituto Scientifico Tumori, Italy
Karl-Johan Malmberg, Oslo University Hospital, Norway

Copyright: © 2012 Rajagopalan and Long. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

*Correspondence: Sumati Rajagopalan, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases/National Institutes of Health, 12441 Parklawn Drive, Rockville, MD 20852, USA. e-mail: