NK cell subsets in health and disease: new developments

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Background

Under physiological conditions, the distribution/intensity of the surface markers CD56 and CD16 (FcγRIII) defines two subsets of NK lymphocytes: the CD56bright/CD16neg-dim (generally referred to as CD56bright) population that make up about 10% of blood NK cells in adults and the CD56dim/CD16bright (generally referred to as CD56dim) cells that comprise for about 90% of circulating NK cells. CD56bright NK cells exert only marginal cytotoxic capacity but are higly proficient in production of cytokines such as interferon IFN-γ, TNF-α and GM-CSF. Because of this property, CD56bright NK cells have been generally referred to as regulatory NK cells.
Conversely, CD56dim NK cells were originally identified as the main subset with a key role in natural and antibody-dependent cellular cytotoxicity (ADCC), although subsequent data indicated that they can also produce relatively high amounts of pro-inflammatory cytokines following the engagement of activating NK receptors. The different functional outcomes of CD56bright and CD56dim NK cells are dependent on the differential expression of a large repertoire of activating and inhibitory receptors, and on the expression of a distinct subset of chemokine receptors that influence NK cell homing. Indeed, CD56dim NK cells preferentially migrate to inflamed peripheral tissues on the basis of their increased expression of CXCR1, CX3CR1 and ChemR23, whereas the CD56bright subset expresses CCR7 and homes mostly to secondary lymphoid organs. Remarkably, recent data indicate that in pathological conditions that include viral infections the CD56dim subset may also de novo express CCR7 and migrate toward lymph nodes.
While these data define distinct functional roles played by CD56bright and CD56dim NK cells, the phylogeny and ontogeny of these human NK subsets remain poorly understood. One hypothesis claims that CD56bright NK subset represent a more immature stage of diferentiation than CD56dim cells. This model of linear differentiation is supported by observations that CD56bright NK cells have longer telomeres than CD56dim NK cells, are more abundant in blood in young subjects and early after hematopoietic stem cell transplantation, and differentiate into CD56dim NK cells in humanized mice engrafted with human hemopoietic stem cells. However, gene tracking data in macaques support a different model whereby CD56bright and CD56dim NK cells represent subsets with a distinct ontogeny. The recent identification of NK progenitors cells whose differentiation profile is restricted to the NK cell lineage may help address this issue.
Furthermore, the early recruitment and activation of cytotoxic NK cells at inflammatory sites raises important questions regarding their potential role in mediating immune responses and in the cross-talk between innate and adaptive immune responses. Importantly, alterations of the distribution and function of NK cell subsets has been observed in many pathological conditions, including inborn errors of immunity, severe and chronic viral infections, and cancer. In some cases, exposure to pathogens, such as human cytomegalovirus in humans and murine cytomegalovirus in mice, has been associated with the generation of memory NK cells expressing a distinctive set of activating receptors (NKG2C and Ly49h, respectively). Recent data indicate that this process is governed by metabolic switches that promote mitophagy. If these data are confirmed, pharmacological manipulation of NK cells might play an important role in promoting more effective anti-tumor and anti-viral immune responses.
This research topic will highlight recent advances in human NK cell biology, with the goal of providing a comprehensive understanding of the complexity of NK cell subsets, their functional role in health and disease, and their potential use and manipulation in the treatment of human disorders.

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