Complex regulation of human NKG2D-DAP10 cell surface expression: opposing roles of the γc cytokines and TGF-β1
- 15 September 2011
- journal article
- Published by American Society of Hematology in Blood
- Vol. 118 (11), 3019-3027
- https://doi.org/10.1182/blood-2011-04-346825
Abstract
Natural killer (NK) cells help protect the host against viral infections and tumors. NKG2D is a vital activating receptor, also expressed on subsets of T cells, whose ligands are up-regulated by cells in stress. Ligation of NKG2D leads to phosphorylation of the associated DAP10 adaptor protein, thereby activating immune cells. Understanding how the expression of NKG2D-DAP10 is regulated has implications for immunotherapy. We show that IL-2 and TGF-β1 oppositely regulate NKG2D-DAP10 expression by NK cells. IL-2 stimulation increases NKG2D surface expression despite a decrease in NKG2D mRNA levels. Stimulation with IL-2 results in a small increase of DAP10 mRNA and a large up-regulation of DAP10 protein synthesis, indicating that IL-2–mediated effects are mostly posttranscriptional. Newly synthesized DAP10 undergoes glycosylation that is required for DAP10 association with NKG2D and stabilization of NKG2D expression. TGF-β1 has an opposite and dominant effect to IL-2. TGF-β1 treatment decreases DAP10, as its presence inhibits the association of RNA polymerase II with the DAP10 promoter, but not NKG2D mRNA levels. This leads to the down-regulation of DAP10 expression and, as a consequence, NKG2D protein as well. Finally, we show that other γc cytokines act similarly to IL-2 in up-regulating DAP10 expression and NKG2D-DAP10 surface expression.Keywords
This publication has 51 references indexed in Scilit:
- Expression, signaling proficiency, and stimulatory function of the NKG2D lymphocyte receptor in human cancer cellsProceedings of the National Academy of Sciences of the United States of America, 2011
- The Interactions of Multiple Cytokines Control NK Cell MaturationThe Journal of Immunology, 2010
- TGF- downregulates the activating receptor NKG2D on NK cells and CD8+ T cells in glioma patientsNeuro-Oncology, 2009
- New insights into the regulation of T cells by γc family cytokinesNature Reviews Immunology, 2009
- DAP10 associates with Ly49 receptors but contributes minimally to their expression and function in vivoEuropean Journal of Immunology, 2009
- Ly49H signaling through DAP10 is essential for optimal natural killer cell responses to mouse cytomegalovirus infectionThe Journal of Experimental Medicine, 2009
- DAP10‐ and DAP12‐associated receptors in innate immunityImmunological Reviews, 2008
- NKG2D-Deficient Mice Are Defective in Tumor Surveillance in Models of Spontaneous MalignancyImmunity, 2008
- Interleukin 15–mediated survival of natural killer cells is determined by interactions among Bim, Noxa and Mcl-1Nature Immunology, 2007
- Activation of NK Cells and T Cells by NKG2D, a Receptor for Stress-Inducible MICAScience, 1999