Inborn errors of human natural killer (NK) cells may affect the development of these cells, their function, or both. There are two broad categories of genetic defects of NK cell development, depending on whether the deficiency is apparently specific to NK cells or clearly affects multiple hematopoietic lineages. We review here recent progress in the genetic dissection of these NK deficiencies (NKDs).
Patients with severe combined immunodeficiencies bearing mutations of adenosine deaminase, adenylate kinase 2, interleukin-2 receptor gamma chain, and Janus kinase 3 genes present NKDs and are prone to a broad range of infections. Patients with GATA binding protein 2 deficiency are susceptible to both mycobacterial and viral infections, and display NKDs and a lack of monocytes. Rare patients with mini chromosomal maintenance 4 deficiency display an apparently selective NKD associated with viral infections, but they also display various nonhematopoietic phenotypes, including adrenal insufficiency and growth retardation.
These studies have initiated a genetic dissection of the development of human NK cells. Further studies are warranted, including the search for genetic causes of NKD in particular. This research may lead to the discovery of molecules specifically controlling the development of NK cells and to improvements in our understanding of the hitherto elusive function of these cells in humans.
aLaboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U980, Necker Hospital for Sick Children
bParis Descartes University, Imagine Institute, Paris, France
cSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, USA
dCenter for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
eCentre d’Immunologie de Marseille-Luminy, INSERM U1104
gAix Marseille Université, UM2
hService d’Immunologie, Assistance Publique – Hôpitaux de Marseille, Hôpital de la Conception, Marseille
iPediatric Hematology-Immunology Unit, Necker Hospital, Paris, France
Correspondence to Emmanuelle Jouanguy, Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U980 and University Paris Descartes, Necker Hospital, 149 rue de Sèvres, 75015 Paris, France. Tel: +33 1 72 60 65 28; e-mail: email@example.com