Adaptive NK cells can persist in patients with GATA2 mutation depleted of stem and progenitor cells

Abstract

Key Points GATA-2 expression is restricted to hematopoietic stem and progenitor cells, leading to NK-cell progenitor deficiency in GATA2 patients. A long-lived or self-renewing pool of adaptive NK cells can persist in patients with GATA2 mutation.

The Broad Spectrum of Human Natural Killer Cell Diversity

“…These adaptive NK cell populations have been mostly extensively characterized in the settings of murine cytomegalovirus (MCMV) and HCMV (Hammer and Romagnani, 2017; Tesi et al, 2016). Indeed adaptive NK cells show an array of functional, phenotypic, epigenetic, and homeostatic differences from cNK cells that warrant their classification as a subset distinct from cNK cells (Corat et al, 2017; Hwang et al, 2012; Schlums et al, 2015; Schlums et al, 2017). …”

“…It remains to be seen if in vivo co-stimulation alters adaptive NK cell functionality (Liu et al, 2016). Lastly, recent studies involving patients with either paroxysmal nocturnal hemoglobinuria or GATA2 deficiency indicate that adaptive NK cells selectively persist in these patients whereas cNK cells are reduced, indicative of unique homeostatic regulatory mechanisms at play (Corat et al, 2017; Schlums et al, 2017). Therefore, adaptive NK cells are very distinct in multiple aspects of their basic biology, implying that they fulfill distinct role(s) in immunity.…”

Emerging insights into human health and NK cell biology from the study of NK cell deficiencies

“…However, it is still unclear how a CD56 bright NK cell may undergo differentiation to a CD56 dim cell, both in terms of regulation of CD56 itself and also the host of receptors and functions associated with this transition. The role that GATA2 plays in NK cell homeostasis can be explained by the finding that the remaining CD56 dim NK cells in GATA2‐deficient patients have an adaptive phenotype identified by down‐regulation of SYK, EAT2, PLZF1, and/or FcεGRγ, suggesting that these are long‐lived and that conventional NK cells have been lost from circulation due to attrition of stem cell precursors from the bone marrow . In addition, there may be effects on NK cell trafficking, given the loss of CXCR4 expression on NK cells from GATA2‐deficient patients .…”

“…Regardless, 82% of patients experienced major infections, and of these, 70% are herpesviral infections that are commonly one of the earliest clinical features of disease . There additionally is a correlation between decreasing NK cell numbers in the periphery and increasing complications of disease, and asymptomatic carriers of GATA2 mutations are often CMV seronegative and have higher frequencies of NK cells in peripheral blood . Taken together, these observations suggest that viral infection in the face of impaired NK cell homeostasis and function contributes to NK cell attrition and progression of disease.…”

“…The identification of a persistent adaptive NK cell population in GATA2‐deficient patients highlights the distinct longevity of these cells and suggests that there may be other cases whether the generation of adaptive cells is either impaired, or where the progressive loss of non‐adaptive cells leads to their selective survival. Identifying an NKD with a specific deficit in adaptive or memory‐like NK cell generation would be informative in understanding their role in control of viral infection and malignancy.…”