The Broad Spectrum of Human Natural Killer Cell Diversity

Abstract

Natural killer (NK) cells provide protection against infectious pathogens and cancer. For decades it has been appreciated that two major NK cell subsets (CD56^bright and CD56^dim) exist in humans and have distinct anatomical localization patterns, phenotypes, and functions in immunity. In light of this traditional NK cell dichotomy, it is now clear that the spectrum of human NK cell diversity is much broader than originally appreciated as a result of variegated surface receptor, intracellular signaling molecule, and transcription factor expression; tissue-specific imprinting; and foreign antigen exposure. The recent discoveries of tissue-resident NK cell developmental intermediates, non-NK innate lymphoid cells, and the capacity for NK cells to adapt and differentiate into long-lived memory cells has added further complexity to this field. Here we review our current understanding of the breadth and generation of human NK cell diversity.

Figure 1. Facets of human NK cell phenotypic diversity

Traditionally, two major subsets of NK cells have been characterized in PB based on their differential expression of CD56 and CD16, termed CD56^bright and CD56^dim. Recent studies have expanded on this definition by characterizing NK cells within additional human tissues each possessing distinct phenotypic profiles as indicated. The CD56^bright cNK cell in the blood shares some common features with several of these non-conventional trNK cell populations, but it is becoming clear that trNK are actually quite distinct functionally as well as immunophenotypically (Björkström et al., 2016; Freud et al., 2014; Melsen et al., 2016). Likewise, we are now appreciating the high amounts of diversity within the CD56^dim cNK cell population, as by the generation of adaptive NK cells in response to environmental stimuli such as virally infected cells or cancer (Björkström et al., 2016; Schlums et al., 2015). While many of these populations share a common CD56^brightCD16⁻ immunophenotype they are not necessarily identical to each other, likely due to the influence of a unique microenvironment in each tissue.

Figure 2. Comprehensive model for the development and diversification of the human NK cell lineage

Generation of human NK cell diversity occurs through a multistep process, portrayed here in six steps. (1) BM-resident HSCs give rise to CD34⁺CD45RA⁺ HPCs that leave the marrow (2) and seed SLTs as well as additional tissue niches supporting the generation of multiple lymphoid lineages (3). Within SLTs, these CD34⁺CD45RA⁺ progenitor cells progressively lose their ability to differentiate into DCs, T cells, as well as additional non-NK helper ILC populations through multiple discrete stages of development that have been characterized extensively ex vivo (Scoville et al., 2017). Upon maturation, cNK cells leave the SLTs and accumulate within the PB to create a pool of functionally mature cNK (4). At birth, NK cell diversity is relatively low (Strauss-Albee et al., 2015). However, as an individual ages the cNK cells come in contact with various environment exposures, such as HCMV-infected or malignant cells (5), which drives increased diversity of the overall PB NK cell population and results in the differentiation and expansion of adaptive NK cells (6). The increase in diversity at step 6 is represented by a change in nuclear color from red (cNK) to blue (adaptive NK cell) by a subset of the cells portrayed at step 4.