Th141 - The Role of CXCR4-CXCL12 in the Migration and Development of Human Natural Killer Cells

Abstract Text: Natural killer (NK) cells play a critical role in controlling viral infection and malignancy and undergo differentiation from multipotent progenitors in secondary lymphoid tissue. Despite dependence on the microenvironment for differentiation, little is known about the cell-cell interactions that promote NK cell trafficking and maturation in tissue. We have identified the chemokine receptor CXCR4 and its ligand CXCL12 as regulators of the cellular interactions between human NK cell precursors and stromal cells that support NK cell development. Using in-vitro NK cell differentiation, we found that treatment of CD34+ precursors with CXCR4 antagonist AMD3100 leads to a lower efficiency of NK cell generation. Since previous work demonstrates the association of cell migration with NK cell development, we interrogated the effect of AMD3100 on NK cell migration. Using live cell imaging, we found that AMD3100 treatment of NK cells or progenitor cells results in altered migratory properties; specifically, decreased arrest and adhesion of cells on CXCL12+ stroma. We confirmed these findings in CXCR4 knockdown NK cell lines. Additional experiments using high resolution microscopy and flow cytometry suggest that integrins interact with CXCR4 in NK cells. High resolution imaging of pediatric tonsil by cyclic immunofluorescence demonstrates CXCL12 in tissue niches that likely support NK cell development. Our data suggests that the CXCR4-CXCL12 interaction is critical for migration and proper development of NK cells. These findings enhance our knowledge of the basic underpinning of NK cell biology and have critical implications for understanding human NK cell deficiencies and the development of NK cell therapies.