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.

Figure 1. Human genes known to affect NK cells in the context of naturally occurring disease.

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).

Figure 2. Schematic of terminal human NK cell differentiation and a proposed role for MCM4.

Human NK cells arise from the HSC in the bone marrow and then progress to pro-, pre-, and immature NK cells (also referred to as stage 1, 2, and 3 NK cells, respectively). The immature NK cell transits to the peripheral lymphoid compartment secondary lymphoid tissues where CD56^bright NK cells predominate. CD56^bright NK cells are also referred to as stage 4 NK cells, and current evidence suggests that they develop in the secondary lymphoid tissues into CD56^dim mature NK cells (stage 5). Key differences between CD56^bright and CD56^dim NK cells are depicted in the schematics of these two cells. Characteristics of early-stage NK cells as well as their specific transcriptional requirements are reviewed elsewhere (18). The present work suggests a role for MCM4 in the transition of CD56^bright to CD56^dim NK cells, as evidenced by the relative absence of CD56^dim NK cells in the peripheral blood with the preservation of the CD56^bright NK cell population.