Heterogeneity of human bone marrow and blood natural killer cells defined by single-cell transcriptome

Robert Burns,James W Verbsky,Monica S Thakar,Sridhar Rao,Subramaniam Malarkannan,Zachary J Gerbec,Chao Yang,Amy Rymaszewski,Jason R Siebert,John M Routes,Karen-Sue Carlson,Matthew J Riese,Benedetta Bonacci,Mary Rau

doi:10.1038/s41467-019-11947-7

Robert Burns, James W Verbsky + Show 12 more

Open Access

https://doi.org/10.1038/s41467-019-11947-7

Copy DOI

Abstract

Natural killer (NK) cells are critical to both innate and adaptive immunity. However, the development and heterogeneity of human NK cells are yet to be fully defined. Using single-cell RNA-sequencing technology, here we identify distinct NK populations in human bone marrow and blood, including one population expressing higher levels of immediate early genes indicative of a homeostatic activation. Functionally matured NK cells with high expression of CX3CR1, HAVCR2 (TIM-3), and ZEB2 represents terminally differentiated status with the unique transcriptional profile. Transcriptomic and pseudotime analyses identify a transitional population between CD56bright and CD56dim NK cells. Finally, a donor with GATA2T354M mutation exhibits reduced percentage of CD56bright NK cells with altered transcriptome and elevated cell death. These data expand our understanding of the heterogeneity and development of human NK cells.

Highlights

Natural killer (NK) cells are critical to both innate and adaptive immunity
We utilized scRNA-sequencing technology to explore the heterogeneity of human NK cells from both bone marrow (BM) and blood of healthy donors and a donor with GATA2T354M mutation
Half of them marked with high expression of CX3CR1, HAVCR2 (TIM-3), and ZEB2 demonstrate unique transcriptional features and may comprise the terminal mature NK cells

Summary

Introduction

Natural killer (NK) cells are critical to both innate and adaptive immunity. the development and heterogeneity of human NK cells are yet to be fully defined. The CD56dim NK population is further divided into two groups based on the expression of CD57, where CD57+ cells form a terminally mature subset with a greater killing capacity[20,21] In contrast to this simple CD56- and CD57based (CD56bright → CD56dimCD57− → CD56dimCD57+) developmental paradigm, mass cytometry (CyTOF)-based immune profiling has revealed thousands of phenotypically distinct NK cells depending on the combinatorial expression of 28 cell surface receptors[22]. This contrast emphasizes the importance of further defining the heterogeneity of the NK population using other modalities, including underlying transcriptional divergence. Our data provide a transcriptome-based definition of the heterogeneity and development of human NK cells

Methods

Results

Conclusion