Location and cellular stages of natural killer cell development

Abstract

The identification of distinct tissue-specific natural killer (NK) cell populations that apparently mature from local precursor populations has brought new insight into the diversity and developmental regulation of this important lymphoid subset. NK cells provide a necessary link between the early (innate) and late (adaptive) immune responses to infection. Gaining a better understanding of the processes that govern NK cell development should allow us to harness better NK cell functions in multiple clinical settings, as well as to gain further insight into how these cells undergo malignant transformation. In this review, we summarize recent advances in understanding sites and cellular stages of NK cell development in humans and mice.

Keywords: NK development; hematopoiesis; innate lymphoid cell; lymphopoiesis; natural killer; stages of maturation.

Figure 1. Schematic representation of the cellular intermediates of human NK cell development

Human NK cell development from hematopoietic stem cell (HSC) to mature stage 5 CD56^dim NK cell is represented as a linear pathway from left to right. Memory NK cells are depicted as a possible terminal stage of maturation (stage 6), with experimental evidence that memory NK cells may be derived from CD56^bright as well as CD56^dim NK cells [87]. Of note, memory NK cells are depicted here as one population although evidence to date indicates that there are at least three distinct pathways of NK cell memory formation [88]. Shown for each developmental stage is the expression of each surface antigen useful in distinguishing populations of NK developmental intermediates. Expression is designated as “+” (expression), “−” (no expression), “hi” (high expression), or “lo” (low expression).

Figure 2. Schematic representation of the cellular intermediates of mouse NK cell development

Mouse NK cell development from hematopoietic stem cell (HSC) to mature CD11b^highDX5⁺ NK cell is represented as a linear pathway from left to right. Memory NK cells are depicted as a possible terminal stage of maturation, and memory NK cells are depicted here as one population although evidence to date indicates that there are at least three distinct pathways of NK cell memory formation [88]. Shown for each developmental stage is the expression of each surface antigen useful in distinguishing populations of NK developmental intermediates. Expression of each antigen in a particular stage is designated as “+” (expression), “−” (no expression), “hi” (high expression), or “lo” (low expression). CLP – common lymphoid progenitor, NKP –NK cell precursor, iNK – immature NK cell, mNK – mature NK cell.

Figure 3. Extramedullary human NK cell development as a means of generating functionally distinct and tissue-specific NK cells

CD34⁺CD45RA⁺ NK cell developmental intermediates (NKDI) with ex vivo potential for NK cell differentiation are present in and likely originate within human bone marrow, but they are also present as normal constituents of circulating peripheral blood and extramedullary tissue leukocytes. In humans, IL-15-responsive CD34⁺CD45RA⁺ NKDI comprise a relatively higher proportion of total CD34+ progenitor cells (5–10%) in the blood compared to bone marrow (<1%), and in SLT they comprise the major subset of CD34+ HPC (>90%) [36]. Similar CD34⁺ HPC have been detected in MALT, liver, and the gravid uterus where downstream NK cell developmental intermediates have also been identified [–146]. Given the evidence for functionally distinct NK cell subsets in these various tissues as well as in the thymus [2, 6, 13, 124, 152], the findings support a model whereby CD34⁺CD45RA⁺ NKDI originate in the bone marrow and traffic to extramedullary tissues where they give rise to tissue-specific and functionally distinct mature NK cell subsets.