Diversification of human NK cells: Lessons from deep profiling

Abstract

NK cells are innate lymphocytes with important roles in immunoregulation, immunosurveillance, and cytokine production. Originally defined on the functional basis of their "natural" ability to lyse tumor targets and thought to be a relatively homogeneous group of lymphocytes, NK cells possess a remarkable degree of phenotypic and functional diversity due to the combinatorial expression of an array of activating and inhibitory receptors. Diversification of NK cells is multifaceted: mechanisms of NK cell education that promote self-tolerance result in a heterogeneous repertoire that further diversifies upon encounters with viral pathogens. Here, we review the genetic, developmental, and environmental sources of NK cell diversity with a particular focus on deep profiling and single-cell technologies that will enable a more thorough and accurate dissection of this intricate and poorly understood lymphocyte lineage.

Keywords: NK cell; host-pathogen interaction; innate lymphoid cell; lymphocyte diversity; mass cytometry; single-cell technology.

Figure 1:

Human NK cell repertoire shifts and expansions induced by particular viral infections. The inexperienced NK cell repertoire begins as a collection of relatively homogenous cytokine-producing CD56^bright NK cells, and CD16⁺KIR⁺ cytotoxic CD56^dim NK cells. These subsets differentiate and diversify in response to various viral infections. EBV expands a population of early-differentiated CD16⁺KIR^-NKG2A⁺ CD56^dim NK cells which gradually acquire KIRs through education. HCMV, on the other hand, induces expansion of late-differentiated CD57⁺NKG2C⁺ NK cells. Chronic infection, in particular by HIV or HCV, can induce the formation of anergic CD56^neg NK cells. It is important to note that, while specific expansions or subsets are depicted as single cells, virus-induced changes in NKR expression typically correspond to repertoire-wide changes and not necessarily specific populations. Here, a darker arrow corresponds to a more conclusive relationship between the two NK cell subsets. For example, it remains unclear if CD56^bright NK cells represent CD56^dim precursors in vivo.