Abstract
Natural killer (NK) cells are effector cells of the innate immune system involved in defense against virus-infected and transformed cells. The effector function of NK cells is linked to their ability to migrate to sites of inflammation or damage. Therefore, understanding the factors regulating NK cell migration is of substantial interest. Here, we show that in the absence of aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, NK cells have reduced capacity to migrate and infiltrate tumors in vivo. Analysis of differentially expressed genes revealed that ankyrin repeat and SOCS Box containing 2 (Asb2) expression was dramatically decreased in Ahr –/– NK cells and that AhR ligands modulated its expression. Further, AhR directly regulated the promoter region of the Asb2 gene. Similar to what was observed with murine Ahr –/– NK cells, ASB2 knockdown inhibited the migration of human NK cells. Activation of AHR by its agonist FICZ induced ASB2-dependent filamin A degradation in NK cells; conversely, knockdown of endogenous ASB2 inhibited filamin A degradation. Reduction of filamin A increased the migration of primary NK cells and restored the invasion capacity of AHR-deficient NK cells. Our study introduces AHR as a new regulator of NK cell migration, through an AHR-ASB2-filamin A axis and provides insight into a potential therapeutic target for NK cell-based immunotherapies.
Highlights
Natural killer (NK) cells are innate lymphocytes that belong to the Group 1 innate lymphoid cell (ILC) family and are able to respond rapidly to virally infected or transformed cells [1]
Time-lapse microscopy of NK cells in an in vitro 3D extracellular matrix (ECM)-like culture system showed that Ahr–/– NK cells had lower migration speed, lower migratory distance and lower invasion capacity compared to WT NK cells (Figures 1B–D)
ASB2 regulates the accumulation of filamin A through a ubiquitin-mediated proteasome degradation pathway, which modulates NK cell migration
Summary
Natural killer (NK) cells are innate lymphocytes that belong to the Group 1 innate lymphoid cell (ILC) family and are able to respond rapidly to virally infected or transformed cells [1]. The function of NK cells is controlled by an array of germline-encoded receptors that enable them to sample the microenvironment and rapidly exert their effector functions without the need of prior stimulation [2]. Trafficking of NK cells from blood into tissue compartments, including the tumor microenvironment, is regulated by chemokines and cytokines. NK cells express several chemokine receptors, such as CCR5, CCR7, CXCR3, CXCR4, CXCR6, CCR7 [reviewed in [5]], whose expression is essential for the tissue tropism of NK cells and their interaction with other cell types. IL-2 and IL15 induce homing of NK cells to tissues [6], whereas TGF-b impairs their migration [7, 8]. Transcription factors, like T-bet [9], regulate the ability of NK cells to migrate
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
