The stage-specific effects of IL-1β on human natural killer cell development

Our laboratory previously demonstrated that natural killer (NK) cell developmental intermediates can be found in secondary lymphoid tissue (SLT) (Freud, Becknell et al. 2005). Our subsequent study detailed the surface phenotype of SLT NK progenitor and precursor populations, provided a paradigm for NK ontogeny, and demonstrated that NK development progresses in a unidirectional manner through four discrete developmental stages (Freud, Yokohama et al. 2006). Stage 3 cells, which are exclusively committed to the NK lineage, were characterized as a population of immature NK (iNK) cells because they lack certain characteristics of mature NK cells, including some NK cell surface receptors, cytolytic activity, and the capacity for interferon-gamma (IFN-γ) production. It has already been documented that interleukin (IL)-15 is crucial for mature NK cell function (Carson, Giri et al. 1994), survival (Cooper, Bush et al. 2002), and for normal NK cell development (Yu, Fehniger et al. 1998); however, only a small fraction [~2-20%] of stage 3 iNK cells become stage 4 mature NK cells in response to IL-15 in vitro (Freud, Yokohama et al. 2006). Thus, the identity of the immunomodulatory factors regulating stage 3 iNK cell expansion and differentiation may not yet be fully elucidated. For the past four years, this topic has been the focus of my research.

Through the course of many studies, we (myself along with my collaborators) have discovered that the IL-1 receptor (IL-1R1) is selectively expressed by a subpopulation of stage 3 iNK cells. We also discovered that the vast majority of stage 3 iNK cells in SLT constitutively and selectively express aryl hydrocarbon receptor (AHR) and IL-22, a T_H17 cytokine which may have an important role in maintaining mucosal immunity. IL-1R1, AHR, and IL-22 expression were absent during earlier and later stages of NK development, and expression of AHR and IL-22 were largely restricted to the IL-1R1^hi subpopulation of stage 3 iNK cells.

These IL-1R1^hi stage 3 iNK cells localized proximal to IL-1β-producing conventional dendritic cells (cDC) within SLT, proliferated in direct response to cDC-derived IL-15 and IL-1β, and required continuous exposure to IL-1β to retain AHR and IL-22 expression. In the absence of IL-1β, a substantially greater fraction of IL-1R1^hi stage 3 iNK cells differentiated to stage 4 mature NK cells, and acquired the ability to kill and secrete IFN-γ. Thus, cDC-derived IL-1β preserves and expands IL-1R1^hiIL-22⁺AHR⁺ stage 3 iNK cells, potentially influencing human mucosal innate immunity during infection.

These data support a role for IL-1β as an immunomodulatory factor capable of regulating the development of human NK cells in vivo, and also suggest that these “immature” NK cells may have a unique functional role within SLT. Herein, I present these findings and provide an extended discussion relating our new data to current concepts in the field of NK cell developmental biology.