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

Abstract

Human NK cells are innate immune effectors that play a critical roles in the control of viral infection and malignancy. The importance of their homeostasis and function can be demonstrated by the study of patients with primary immunodeficiencies (PIDs), which are part of the family of diseases known as inborn defects of immunity. While NK cells are affected in many PIDs in ways that may contribute to a patient's clinical phenotype, a small number of PIDs have an NK cell abnormality as their major immunological defect. These PIDs can be collectively referred to as NK cell deficiency (NKD) disorders and include effects upon NK cell numbers, subsets, and/or functions. The clinical impact of NKD can be severe including fatal viral infection, with particular susceptibility to herpesviral infections, such as cytomegalovirus, varicella zoster virus, and Epstein-Barr virus. While NKD is rare, studies of these diseases are important for defining specific requirements for human NK cell development and homeostasis. New themes in NK cell biology are emerging through the study of both known and novel NKD, particularly those affecting cell cycle and DNA damage repair, as well as broader PIDs having substantive impact upon NK cells. In addition, the discovery of NKD that affects other innate lymphoid cell (ILC) subsets opens new doors for better understanding the relationship between conventional NK cells and other ILC subsets. Here, we describe the biology underlying human NKD, particularly in the context of new insights into innate immune cell function, including a discussion of recently described NKD with accompanying effects on ILC subsets. Given the impact of these disorders upon human immunity with a common focus upon NK cells, the unifying message of a critical role for NK cells in human host defense singularly emerges.

Keywords: innate lymphoid cell; natural killer cell; natural killer cell deficiency; primary immunodeficiency.

Figure 1.. Human NK cell and ILC developmental subsets and NK cell/ILC deficiencies that affect them.

Key cell surface receptors that identify NK cell and ILC developmental subsets are shown. Monogenic causes of NKD or ILC deficiency are shown in red. This model of human NK cell development is adapted from^,, with circulating ILC subsets and precursors shown as described in Cottineau et al to be affected in some patients with GINS1 mutations. Lineage markers are CD3, CD4, CD5, CD14, CD16, CD94, CD123, CD34, CD303, CD19, FcεR1α. **IL-17 producing subset only. ILCP, systemic innate lymphoid cell precursor. Dashed line indicates inferred relationship, solid line indicates experimentally defined relationships.

Figure 2.. Herpesviral susceptibility is a unifying feature of human NK cell deficiencies.

Within the >350 primary immunodeficiencies registered by the International Union of Immunological Societies, an effect on NK cell function or phenotype has been noted in >50 of these (left). There are currently 6 published monogenic causes of human NK cell deficiency, in which disrupted NK cell development is the sole or predominant feature. While these may have other clinical features, the underlying clinical theme is that of viral susceptibility, particularly severe or refractory herpesviral infections (right). Despite the diverse functions of these genes, this shared susceptibility to viral infection, particularly by herpesviruses, underscores the common theme of NK cell deficiency amongst each of these defects and therefore the critical role that human NK cells play in antiviral immunity.