title: Multi-cellular natural killer (NK) cell clusters enhance NK cell activation through localizing IL-2 within the cluster.
abstract: Multi-cellular cluster formation of natural killer (NK) cells occurs during in vivo priming and potentiates their activation to IL-2. However, the precise mechanism underlying this synergy within NK cell clusters remains unclear. We employed lymphocyte-laden microwell technologies to modulate contact-mediated multi-cellular interactions among activating NK cells and to quantitatively assess the molecular events occurring in multi-cellular clusters of NK cells. NK cells in social microwells, which allow cell-to-cell contact, exhibited significantly higher levels of IL-2 receptor (IL-2R) signaling compared with those in lonesome microwells, which prevent intercellular contact. Further, CD25, an IL-2R α chain, and lytic granules of NK cells in social microwells were polarized toward MTOC. Live cell imaging of lytic granules revealed their dynamic and prolonged polarization toward neighboring NK cells without degranulation. These results suggest that IL-2 bound on CD25 of one NK cells triggered IL-2 signaling of neighboring NK cells. These results were further corroborated by findings that CD25-KO NK cells exhibited lower proliferation than WT NK cells, and when mixed with WT NK cells, underwent significantly higher level of proliferation. These data highlights the existence of IL-2 trans-presentation between NK cells in the local microenvironment where the availability of IL-2 is limited.
authors.affiliation: School of Interdisciplinary Bioscience and Bioengineering (I-Bio), Pohang University of Science and Technology, Pohang, Gyeongbuk 790-784, Korea.|Amore-Pacific R&D Centre, Yongin, 17074, Korea.
authors.forename: Miju
authors.initials: M
authors.lastname: Kim
authors.affiliation: Global Research Lab, Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul 136-713, Korea.
authors.forename: Tae-Jin
authors.initials: TJ
authors.lastname: Kim
authors.affiliation: Division of Integrative Biosciences and Biotechnology (IBB), Pohang University of Science and Technology, Pohang, Gyeongbuk 790-784, Korea.
authors.forename: Hye Mi
authors.initials: HM
authors.lastname: Kim
authors.affiliation: School of Interdisciplinary Bioscience and Bioengineering (I-Bio), Pohang University of Science and Technology, Pohang, Gyeongbuk 790-784, Korea.|Department of Mechanical Engineering, Pohang University of Science and Technology, Pohang, Gyeongbuk 790-784, Korea.
authors.forename: Junsang
authors.initials: J
authors.lastname: Doh
authors.affiliation: Global Research Lab, Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul 136-713, Korea.|Department of Melanoma Medical Oncology and Immunology, MD Anderson Cancer Center, Houston, Texas 77054, United States.
authors.forename: Kyung-Mi
authors.initials: KM
authors.lastname: Lee
mesh_terms: D000818:Animals; D002449:Cell Aggregation; D002450:Cell Communication; D016764:Cell Polarity; D049109:Cell Proliferation; D007376:Interleukin-2 / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D008810:Mice, Inbred C57BL; D022101:Microtubule-Organizing Center / Q000378:metabolism; D015398:Signal Transduction; D059010:Single-Cell Analysis
chemical_list: D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit