The introduction of new technologies and their application to biological questions has enhanced our understanding of a range of topics. For example, cytometry by time of flight (CyTOF; also known as mass cytometry) has transformed ideas about the immune system. In a study published in 2013, Horowitz et al. used mass cytometry to investigate the exquisite variety of natural killer (NK) cells, revealing the complexity of expression of activating and inhibitory receptors on their surface. The myriad of phenotypes they describe bring to light new questions regarding NK cell maturation, functionality and memory potential.

At the start of the 21st century, a great deal was still unknown about the regulation and expression of NK cell receptors and the mechanisms underlying NK cell function and tolerance. It had been speculated that any combination of the many germline-encoded activating and inhibitory receptors would function as a rheostat to increase or decrease sensitivity of the NK cell for activation. Horowitz et al. show that the NK cell repertoire is ‘anchored’ by the expression of a small number of receptors (CD16–CD57 and NKG2A–CD94) that account for the only major subdivision of NK cells, upon which the immense diversity of phenotypes is built through the stochastic expression of all other NK cell receptors.

This paper also shows, for the first time, that the receptor expression of peripheral NK cells is influenced by the environment, providing evidence that these innate cells can adapt. By comparing the phenotypic variation of NK cells between monozygotic twins with the variation between genetically diverse individuals, the authors suggest that whereas inhibitory receptor expression seems to be bound by the genetic code, activating receptor expression may be influenced by environmental cues in the periphery. Viral infection is one way in which the activating receptor expression of NK cells may be altered, and the authors describe the presence of a common receptor expression cluster (CD57+NKG2C+) on a subset of NK cells in individuals infected with cytomegalovirus. It is thought that this phenotype identifies a subset of memory NK cells; thus, these data provide further support for the existence of innate cell memory (Goodier et al., 2007; Lopez-Vergès et al., 2011).

Overall, this paper highlights how the unbiased collection of high resolution data can refine models and provide a new framework within which investigators can study the mechanisms underlying NK cell functionality.