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Blood, 15 February 2006, Vol. 107, No. 4, pp. 1468-1475.
Prepublished online as a Blood First Edition Paper on October 25, 2005; DOI 10.1182/blood-2005-04-1579.
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IMMUNOBIOLOGY
Regulation of ITAM-positive receptors: role of IL-12 and IL-18
John R. Ortaldo,
Robin Winkler-Pickett,
Jon Wigginton,
Meagan Horner,
Earl W. Bere,
Anna T. Mason,
Narayan Bhat,
James Cherry,
Michael Sanford,
Deborah L. Hodge, and
Howard A. Young
From the Laboratory of Experimental Immunology and Pediatric Oncology Branch, National Cancer Institute-Center for Cancer Research, Frederick; and SAIC-Frederick, Frederick, MD.
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- 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- 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.
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