Novel APC-like properties of human NK cells directly regulate T cell activation
Jacob Hanna, … , Jane H. Buckner, Ofer Mandelboim
Jacob Hanna, … , Jane H. Buckner, Ofer Mandelboim
Published December 1, 2004
Citation Information: J Clin Invest. 2004;114(11):1612-1623. https://doi.org/10.1172/JCI22787.
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Article Immunology

Novel APC-like properties of human NK cells directly regulate T cell activation

Abstract

Initiation of the adaptive immune response is dependent on the priming of naive T cells by APCs. Proteomic analysis of unactivated and activated human NK cell membrane–enriched fractions demonstrated that activated NK cells can efficiently stimulate T cells, since they upregulate MHC class II molecules and multiple ligands for TCR costimulatory molecules. Furthermore, by manipulating antigen administration, we show that NK cells possess multiple independent unique pathways for antigen uptake. These results highlight NK cell–mediated cytotoxicity and specific ligand recognition by cell surface–activating receptors on NK cells as unique mechanisms for antigen capturing and presentation. In addition, we analyzed the T cell–activating potential of human NK cells derived from different clinical conditions, such as inflamed tonsils and noninfected and CMV-infected uterine decidual samples, and from transporter-associated processing antigen 2–deficient patients. This in vivo analysis revealed that proinflammatory, but not immune-suppressive, microenvironmental requirements can selectively dictate upregulation of T cell–activating molecules on NK cells. Taken together, these observations offer new and unexpected insights into the direct interactions between NK and T cells and suggest novel APC-like activating functions for human NK cells.

Authors

Jacob Hanna, Tsufit Gonen-Gross, Jonathan Fitchett, Tony Rowe, Mark Daniels, Tal I. Arnon, Roi Gazit, Aviva Joseph, Karoline W. Schjetne, Alexander Steinle, Angel Porgador, Dror Mevorach, Debra Goldman-Wohl, Simcha Yagel, Michael J. LaBarre, Jane H. Buckner, Ofer Mandelboim

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Activating NK receptors internalize into MHC class II peptide loading co...
Activating NK receptors internalize into MHC class II peptide loading compartments. (A) ANK cells were labeled with LysoTracker and then incubated with anti-CD16, anti-NKp46, anti-NKp30, and anti-NKG2D mAbs and Cy5-labeled F(ab′)2 goat anti-mouse IgG. NK receptors were visualized by confocal microscopy before (0 minutes) and 30 minutes after induction of internalization at 37_C. CD16 internalization of DCs is shown as a positive control. The lower right corners of merged images indicate the average percentage of cells demonstrating colocalization of NK receptors and endosomal-lysosomal compartments when the cells were visualized at low power. (B) ANK cells were cultured with the indicated mouse mAbs for 24 hours. Subsequently, ANK cells were fixed and introduced to DR4-restricted CD4+ T cells specific for Cκ40–48 epitope (50 × 103 cells per well). After 48 hours of incubation, T cell proliferation and cytokine production were measured. (C) Irradiated ANK cells (5 × 104 per well) were washed and incubated with HA or BSA antigens at different concentrations for 30 minutes on ice, then washed and incubated with anti-NKp46 mAb or anti-CD16 mAb for 45 minutes on ice. The cells were further washed and incubated for 30 minutes with goat anti-mouse F(ab′)2 and washed before addition of 50 × 103 OFR3 clone T cells per well. Cells were cultured for 20 hours and pulsed with [3H]thymidine for an additional 16 hours to measure OFR3 T cell proliferation, in addition to IL-2 and IFN-γ production. Data are representative of 3 separate experiments.