Insights Into Human Intrahepatic NK Cell Function From Single Cell RNA Sequencing Datasets.

Gráinne Jameson,Mark W Robinson

doi:10.3389/fimmu.2021.649311

Abstract

Diverse populations of natural killer (NK) cells have been identified in circulating peripheral blood and a wide variety of different tissues and organs. These tissue-resident NK cell populations are phenotypically distinct from circulating NK cells, however, functional descriptions of their roles within tissues are lacking. Recent advances in single cell RNA sequencing (scRNA-seq) have enabled detailed transcriptional profiling of tissues at the level of single cells and provide the opportunity to explore NK cell diversity within tissues. This review explores potential novel functions of human liver-resident (lr)NK cells identified in human liver scRNA-seq studies. By comparing these datasets we identified up-regulated and down-regulated genes associated with lrNK cells clusters. These genes encode a number of activating and inhibiting receptors, as well as signal transduction molecules, which highlight potential unique pathways that lrNK cells utilize to respond to stimuli within the human liver. This unique receptor repertoire of lrNK cells may confer the ability to regulate a number of immune cell populations, such as circulating monocytes and T cells, while avoiding activation by liver hepatocytes and Kupffer cells. Validating the expression of these receptors on lrNK cells and the proposed cellular interactions within the human liver will expand our understanding of the liver-specific homeostatic roles of this tissue-resident immune cell population.

Highlights

Natural Killer Cells: From Blood to TissuesThe phenotype and function of natural killer (NK) cells have been extensively studied in both mice and humans, predominantly utilizing NK cells isolated from circulating peripheral blood (PB)
Using ligand-receptor pair databases Zhang and colleagues predicted that LAMP3+ dendritic cells (DC) in the liver interact with conventional circulating NK cells via the activating Nectin2-DNAM-I axis and with lrNK cells via inhibitory Nectin-2-T cell Ig and ITIM domain (TIGIT) interactions suggesting that liver DCs may be regulating different NK subsets in opposing directions [85, 86]
We show that scRNA-seq datasets can provide novel insights into possible functional roles of human lrNK cells (Figure 2) that may support the development of novel hypotheses to be explored in future functional investigations, once expression at the protein level is validated

Summary

Introduction

Natural Killer Cells: From Blood to TissuesThe phenotype and function of natural killer (NK) cells have been extensively studied in both mice and humans, predominantly utilizing NK cells isolated from circulating peripheral blood (PB). A variety of activating and inhibitory receptors, downstream signaling molecules, and effector molecules are differentially expressed between lrNK cells and cNK cells (Figure 1 and Supplementary Data). A number of genes involved in the activation of NK cells are differentially regulated in lrNK and cNK cells in these scRNAseq datasets (Figure 1 and Supplementary Data).

Results

Conclusion