Abstract
Recent studies have demonstrated extraordinary diversity in peripheral blood human natural killer (NK) cells and have suggested environmental control of receptor expression patterns on distinct subsets of NK cells. However, tissue localization may influence NK cell differentiation to an even higher extent and less is known about the receptor repertoire of human tissue-resident NK cells. Advances in single-cell technologies have allowed higher resolution studies of these cells. Here, the power of high-dimensional flow cytometry was harnessed to unravel the complexity of NK cell repertoire diversity in liver since recent studies had indicated high heterogeneity within liver NK cells. A 29-color flow cytometry panel allowing simultaneous measurement of surface tissue-residency markers, activating and inhibitory receptors, differentiation markers, chemokine receptors, and transcription factors was established. This panel was applied to lymphocytes across three tissues (liver, peripheral blood, and tonsil) with different distribution of distinct NK cell subsets. Dimensionality reduction of this data ordered events according to their lineage, rather than tissue of origin. Notably, narrowing the scope of the analysis to the NK cell lineage in liver and peripheral blood separated subsets according to tissue, enabling phenotypic characterization of NK cell subpopulations in individual tissues. Such dimensionality reduction, coupled with a clustering algorithm, identified CD49e as the preferred marker for future studies of liver-resident NK cell subsets. We present a robust approach for diversity profiling of tissue-resident NK cells that can be applied in various homeostatic and pathological conditions such as reproduction, infection, and cancer.
Highlights
The last five decades have seen extraordinary developments in the understanding of natural killer (NK) cell biology
Peripheral blood is rich in the CD56dim population and there is generally a lower percentage of circulating CD56bright NK cells
Flow cytometry is a widely-adopted technology used to investigate the dynamics of immune responses
Summary
The last five decades have seen extraordinary developments in the understanding of natural killer (NK) cell biology. NK cells are innate lymphocytes originally discovered as cells capable of killing tumor cells and later virally-infected cells [1, 2]. One of the major pathways of cell death mediated by NK cells involves secretion of cytolytic molecules like perforin and granzymes, which makes NK cells functionally related to their adaptive counterpart, cytotoxic T lymphocytes (CTLs) [3, 4]. NK cells use an array of germlineencoded receptors to carry out their main tasks associated with the recognition of non-self: tumor surveillance and clearance of viral infections [5, 6]. Engagement of distinct activating and inhibitory receptors expressed on the surface of NK cells by their respective ligands determines the functional response. Genetic and environmental determinants shape the overall diversity of these receptors [7]
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