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.

Keywords: development; human lymphopoiesis; innate lymphoid cells; natural killer; secondary lymphoid tissues.

Figure 1

Ex vivo patterns of surface antigen expression support a model of human natural killer (NK) cell development in secondary lymphoid tissues (SLTs). (A) Ex vivo immunophenotypic analyses of CD3⁺ cells (top row, left plots), CD19⁺ cells (top row, right plots), and Lin⁻CD56⁺ cells (bottom row) in the indicated tissues demonstrate how immature T, B, and NK cell developmental intermediates (designated by the red circles and ovals) are naturally enriched in the thymus, bone marrow, and SLTs, respectively. Of note, the SLT populations designated by the red circles in the bottom row also likely contain some ILC3s, which can express CD56 (14). The red arrows in the bottom row highlight the relative enrichment of stage 4b CD56^brightNKp80⁺CD16⁻ NK cells in SLTs. (B) Immunophenotypic analysis of Lin⁻ ILCs in human tonsil demonstrating the two-way patterns of CD34, CD117, CD94, NKp80, and CD16 expression as they relate to one another. The red arrows depict the putative directions of progressive NK cell development in SLTs. (C) Schematic representation of the proposed stages of human NK cell development in SLTs. The stages are defined according to the differential expression of CD34, CD117, interleukin (IL)-1R1, CD94, NKp80, CD16, and CD57, and the red lines underline the surface antigen changes that define each stage transition. Although not depicted, it is noted that CD56 expression is first detected at stage 2b (heterogeneous), peaks at stage 4b (CD56^bright), and then decreases to the level of most peripheral blood NK cells at stage 6 (CD56^dim). Also not depicted is killer immunoglobulin-like receptor expression, which is first detected within stage 4b in SLTs (40).

Figure 2

Models of mouse and human innate lymphoid cell (ILC) development. Shown on the left and right are schematic representations of the cellular intermediates and developmental pathways of mouse and human ILCs, respectively. The black lines represent progressive steps of differentiation and maturation that are currently supported by published data. The dashed lines represent possible steps and relationships of differentiation and maturation, but these have not yet been tested or definitively established. In particular, the relationships between stage 1, 2a, 2b, and 3 cells with NK cell progenitors (NKPs) described by Renoux et al. (65) are not yet known. In addition, the relationship and possible distinction between human stage 3 natural killer (NK) cell precursors and ILC3s is also not yet clear. In the diagram to the right depicting human ILC development, the labels ILC3P (for ILC3 progenitor), ILC2P (for ILC2 progenitor), and ILC1P (for ILC1 progenitor) are shown in parentheses to convey that these are theoretical populations that have not been identified. CILP, common innate lymphoid progenitor; CHILP, common helper innate lymphoid progenitor.