Abstract
B7-H4 is a newly identified B7 homolog that plays an important role in maintaining T-cell homeostasis by inhibiting T-cell proliferation and lymphokine-secretion. In this study, we investigated the signal transduction pathways inhibited by B7-H4 engagement in mouse T cells. We found that treatment of CD3(+) T cells with a B7-H4.Ig fusion protein inhibits anti-CD3 elicited T-cell receptor (TCR)/CD28 signaling events, including phosphorylation of the MAP kinases, ERK, p38, and JNK. B7-H4.Ig treatment also inhibited the phosphorylation of AKT kinase and impaired its kinase activity as assessed by the phosphorylation of its endogenous substrate GSK-3. Expression of IL-2 is also reduced by B7-H4. In contrast, the phosphorylation state of the TCR proximal tyrosine kinases ZAP70 and lymphocyte-specific protein tyrosine kinase (LCK) are not affected by B7-H4 ligation. These results indicate that B7-H4 inhibits T-cell proliferation and IL-2 production through interfering with activation of ERK, JNK, and AKT, but not of ZAP70 or LCK.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies / metabolism
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Antibodies / pharmacology
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Cell Proliferation / drug effects
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Cells, Cultured
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Down-Regulation / drug effects
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Enzyme Activation / drug effects
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Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors*
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Extracellular Signal-Regulated MAP Kinases / metabolism
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JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors*
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JNK Mitogen-Activated Protein Kinases / metabolism
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Mice
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Mice, Inbred BALB C
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Oncogene Protein v-akt / antagonists & inhibitors*
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Oncogene Protein v-akt / metabolism
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Recombinant Fusion Proteins / metabolism
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Recombinant Fusion Proteins / pharmacology
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Signal Transduction / drug effects
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T-Lymphocytes / drug effects*
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T-Lymphocytes / metabolism
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T-Lymphocytes / physiology
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V-Set Domain-Containing T-Cell Activation Inhibitor 1 / metabolism
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V-Set Domain-Containing T-Cell Activation Inhibitor 1 / pharmacology*
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Antibodies
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Recombinant Fusion Proteins
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V-Set Domain-Containing T-Cell Activation Inhibitor 1
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Vtcn1 protein, mouse
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Oncogene Protein v-akt
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Extracellular Signal-Regulated MAP Kinases
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JNK Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases