Abstract：
: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-gamma 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-gamma 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.
journal_name
Bloodjournal_title
Bloodauthors
Ortaldo JR,Winkler-Pickett R,Wigginton J,Horner M,Bere EW,Mason AT,Bhat N,Cherry J,Sanford M,Hodge DL,Young HAdoi
10.1182/blood-2005-04-1579subject
Has Abstractpub_date
2006-02-15 00:00:00pages
1468-75issue
4eissn
0006-4971issn
1528-0020pii
2005-04-1579journal_volume
107pub_type
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