Unraveling human natural killer cell deficiency
Jordan S. Orange
Jordan S. Orange
Published February 22, 2012
Citation Information: J Clin Invest. 2012;122(3):798-801. https://doi.org/10.1172/JCI62620.
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Unraveling human natural killer cell deficiency

Abstract

NK cells are a component of the innate immune system identified in animals as serving an essential role in antiviral immunity. Establishing their role in human health has been challenging, with the most direct insight coming from the study of NK cell–deficient individuals. However, NK cell deficiencies are rare, and more research is needed. In this issue of the JCI, two independent groups of researchers have simultaneously identified the genetic cause of a human NK cell deficiency as mutation in the MCM4 gene, encoding minichromosome maintenance complex component 4. These reports suggest a critical role for the minichromosome maintenance helicase complex in NK cells and NK cell–mediated host defense.

Authors

Jordan S. Orange

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Figure 1

Human genes known to affect NK cells in the context of naturally occurring disease.

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Human genes known to affect NK cells in the context of naturally occurri...
A human NK cell is represented schematically, with disease-associated genes listed in proximity to where the encoded proteins function within the cell. Genes that have an impact on other immune cells in addition to NK cells and thus cause broader immunodeficiency/hematological syndromes are shown in blue. The three genes known to cause either functional (CD16) or classical (GATA2 and now MCM4) NK cell deficiency are shown in red. CD16 mutation impacts a region of the well-defined NK cell activation receptor (shown on the cell surface) encoded by the gene (9), while GATA2 mutation affects the broadly expressed hematopoietic transcription factor (shown in the nucleus) that it encodes (10, 11). MCM4 mutations as defined by Gineau et al. (12) and Hughes et al. (13) presumably affect the function in NK cell DNA replication of the MCM2–7 complex of which MCM4 is a component. The impact and role in NK cells of the other human disease-associated mutated genes is reviewed elsewhere (2, 4, 5). In addition to having an impact on other immune cells, these affect NK cell development (IL2RG, JAK3), NK cell survival (ADA, BLM, FANCA–G), NK cell lytic function (ITGB2, ORAI1, LYST, AP3B1, MAPBPIP, RAB27A, UNC13D, STXBP2, STX11, PRF1, CTSC, WASP, MYH9), or NK cell responsiveness (TAP1, TAP2, IL12RB1, NEMO, CASP8).