Human NK cell development requires CD56-mediated motility and formation of the developmental synapse.

Emily M Mace,Justin T Gunesch,Amera Dixon,Jordan S Orange

doi:10.1038/ncomms12171

Emily M Mace, Justin T Gunesch + Show 2 more

Open Access

https://doi.org/10.1038/ncomms12171

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Abstract

While distinct stages of natural killer (NK) cell development have been defined, the molecular interactions that shape human NK cell maturation are poorly understood. Here we define intercellular interactions between developing NK cells and stromal cells which, through contact-dependent mechanisms, promote the generation of mature, functional human NK cells from CD34+ precursors. We show that developing NK cells undergo unique, developmental stage-specific sustained and transient interactions with developmentally supportive stromal cells, and that the relative motility of NK cells increases as they move through development in vitro and ex vivo. These interactions include the formation of a synapse between developing NK cells and stromal cells, which we term the developmental synapse. Finally, we identify a role for CD56 in developmental synapse structure, NK cell motility and NK cell development. Thus, we define the developmental synapse leading to human NK cell functional maturation.

Highlights

While distinct stages of natural killer (NK) cell development have been defined, the molecular interactions that shape human NK cell maturation are poorly understood
Each had a distinct pattern of motility on stroma, with CD56dim NK cells moving in rapid, linear tracks, CD56bright NK cells moving in shorter, multi-directional tracks and CD56neg NK cells demonstrating minimal migration (Fig. 1a; Supplementary Movies 1–3)
The directed shaping of this process is hindered by our lack of understanding of the molecular signalling and intercellular interaction that leads to NK cell development

Summary

Introduction

While distinct stages of natural killer (NK) cell development have been defined, the molecular interactions that shape human NK cell maturation are poorly understood. We define intercellular interactions between developing NK cells and stromal cells which, through contact-dependent mechanisms, promote the generation of mature, functional human NK cells from CD34 þ precursors. Pioneering work on NK cell intermediates in human lymph node described five distinct phenotypes corresponding to linear stages of NK cell development[2,3] While this has been refined in light of the discovery and characterization of innate lymphoid cells, the molecular basis for the supportive nature of the lymph node microenvironment (or nurturing environment) is not known. The role of FGFR1 in CD56bright to CD56dim transition implicates CD56 in this process, as NCAM–FGFR1 interactions in neural cells are well described, this was not directly tested[9]

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