The downside of human natural killer cell diversity in viral infection revealed by mass cytometry

Antigen-specific receptor diversity is the hallmark of an immune cell and an asset in adaptive immunity (1). In contrast, natural killer (NK) diversity appears to be detrimental to its antiviral immune functions, as reported by Strauss-Albee and colleagues (2). Adaptive T and B cell diversity is generated by the rearrangement of their receptors during development, giving rise to a vast array of antigen specificities (3). It is estimated that the total diversity of T cell receptors (TCR) generated by somatic recombination in human T cells is in the order of 10¹⁵–10²⁰ sequences (4). Unlike these adaptive immune cells, innate immune cell diversity, including NK cells, is shaped by random assortment of germline-encoded cell surface receptors. NK cell receptors come in two flavours: activating and inhibitory. Unlike T cell activation, which is mediated by the engagement of TCR and co-stimulatory receptors, NK cell activation is determined by the net balance of signals from the engagement of activating and inhibitory receptors (5). Therefore, the diversity and cell surface expression of these receptors on a per-cell basis can have a profound influence on an NK cell’s function.