Modeling Human Natural Killer Cell Development in the Era of Innate Lymphoid Cells

Abstract

Decades after the discovery of natural killer (NK) cells, their developmental pathways in mice and humans have not yet been completely deciphered. Accumulating evidence indicates that NK cells can develop in multiple tissues throughout the body. Moreover, detailed and comprehensive models of NK cell development were proposed soon after the turn of the century. However, with the recent identification and characterization of other subtypes of innate lymphoid cells (ILCs), which show some overlapping functional and phenotypic features with NK cell developmental intermediates, the distinct stages through which human NK cells develop from early hematopoietic progenitor cells remain unclear. Thus, there is a need to reassess and refine older models of NK cell development in the context of new data and in the era of ILCs. Our group has focused on elucidating the developmental pathway of human NK cells in secondary lymphoid tissues (SLTs), including tonsils and lymph nodes. Here, we provide an update of recent progress that has been made with regard to human NK cell development in SLTs, and we discuss these new findings in the context of contemporary models of ILC development.

The Broad Spectrum of Human Natural Killer Cell Diversity

“…While these questions will undoubtedly be investigated in the coming years, numerous recent studies support a linear model for the development of cNK cells and upon which we can begin to overlay and formulate a working comprehensive model for the generation of all human NK cell subsets characterized to date (Figure 2) (Bjorkstrom et al, 2010; Freud et al, 2016; Freud et al, 2006; Grzywacz et al, 2006; Lopez-Verges et al, 2010; Scoville et al, 2016). According to the linear model of cNK cell development (Scoville et al, 2017), BM-resident HSCs give rise to rare multipotent CD34 + CD45RA + HPCs that then leave the BM, traffic through the PB, and eventually gain entry into SLTs through their preferentially high expression of CD62L, integrin α 4 β 7 , and LFA-1 (Freud et al, 2005). It is likely that the same multipotent HPCs, which have T cell differentiation potential (Freud et al, 2006), can also seed other tissues including the thymus where in the latter they would be diverted by the thymic microenvironment to differentiate into T cells.…”

“…Pertaining to the diversity theme of this piece, one implication of the aforementioned development model is that every NK cell progresses through a CD94/NKG2A + stage 4a intermediate that lacks KIRs as well as CD94/NKG2C expression (Table 1) (Freud et al, 2016; Scoville et al, 2017). Given that many stage 5 and stage 6 CD56 dim cNK cells in PB lack CD94/NKG2A expression and instead express different KIR isoforms and variable amounts of CD94/NKG2C, this implies that as a group cNK cells start out uniform in their MHC class I-binding receptor expression profile (i.e.…”

“…(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).…”

Diversification of human NK cells: Lessons from deep profiling

“…NK cells develop in the bone marrow and secondary lymphoid tissues in discrete stages that have been well characterized [45–51]. After several precursor stages, immature NK cells gain expression of CD56, CD94/NKG2A, and several activating receptors including NKp46, NKp30, and NKG2D.…”

“…These cells, called CD56 bright NK cells, are highly proliferative, capable of producing high amounts of IFN-γ, and express IL-7Rɑ and KIT, two surface markers associated with non-NK ILCs [3,52,53]. In humans, CD56 bright NK cells are hypothesized to give rise to CD56 dim NK cells during the process of education; this involves a decrease in CD56 expression coupled with increased expression of CD16 and acquisition of KIRs [45,48,54]. CD56 dim NK cells are potently cytotoxic, but have substantially lower proliferative and cytokine-producing capacity than their CD56 bright counterparts.…”