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

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.