Regulation of ITAM-positive receptors: role of IL-12 and IL-18

Our previous studies have identified mechanisms by which cytokine production, blocked by Ly49G2 receptor cross-linking, can be overridden. In this study we analyzed the regulation of other ITAM-positive receptor signaling on NK, NKT, and T cells and characterized the biochemical pathways involved in...

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Bibliographic Details
Published in:Blood 2006-02, Vol.107 (4), p.1468-1475
Main Authors: Ortaldo, John R., Winkler-Pickett, Robin, Wigginton, Jon, Horner, Meagan, Bere, Earl W., Mason, Anna T., Bhat, Narayan, Cherry, James, Sanford, Michael, Hodge, Deborah L., Young, Howard A.
Format: Article
Language:English
Subjects:
Amino Acid Substitution
Animals
Antigens, Ly - genetics
Antigens, Ly - immunology
Biological and medical sciences
Cell Line
Cytokines - analysis
Flow Cytometry
Fundamental and applied biological sciences. Psychology
Fundamental immunology
Immunobiology
Interferon-gamma - genetics
Interleukin-12 - pharmacology
Interleukin-18 - immunology
Interleukin-18 - pharmacology
Killer Cells, Natural - drug effects
Killer Cells, Natural - immunology
Lectins, C-Type - genetics
Lectins, C-Type - immunology
Mice
Mice, Inbred BALB C
Modulation of the immune response (stimulation, suppression)
NK Cell Lectin-Like Receptor Subfamily K
Polymerase Chain Reaction
Receptors, Immunologic - genetics
Receptors, Immunologic - immunology
Receptors, Natural Killer Cell
Receptors, NK Cell Lectin-Like
Ribonucleases
T-Lymphocytes - drug effects
T-Lymphocytes - immunology
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Summary:Our previous studies have identified mechanisms by which cytokine production, blocked by Ly49G2 receptor cross-linking, can be overridden. In this study we analyzed the regulation of other ITAM-positive receptor signaling on NK, NKT, and T cells and characterized the biochemical pathways involved in this signaling. Our studies demonstrate that cross-linking of NKG2D and NK1.1 results in a synergistic NK IFN-γ response when combined with IL-12 or IL-18. Examination of NKT- and T-cell responses demonstrated that cross-linking of NKG2D and CD3 resulted in potent synergy when combined with IL-12 and, to a lesser degree, with IL-18. We have now found that both the p38 MAP kinase and the ERK-dependent signal transduction pathways are required for the synergistic response. Further mechanistic examination of the synergy indicated a potent up-regulation of total IFN-γ mRNA in the nuclear and the cytoplasmic compartment, but mRNA half-life was not affected. Fifteen minutes of IL-12 pretreatment was sufficient to result in maximal synergistic activation, indicating that the response of the cells to the IL-12 signal was rapid and immediate. Thus, our data demonstrate that multiple convergent signals maximize the innate immune response by triggering complementary biochemical signaling pathways.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2005-04-1579