title: B7-H4 Treatment of T Cells Inhibits ERK, JNK, p38, and AKT Activation.
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.
authors.affiliation: Department of Surgery, University of British Columbia, Vancouver, Canada.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Wang
authors.forename: Jianqiang
authors.initials: J
authors.lastname: Hao
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Metzger
authors.forename: Ziliang
authors.initials: Z
authors.lastname: Ao
authors.forename: Lieping
authors.initials: L
authors.lastname: Chen
authors.forename: Dawei
authors.initials: D
authors.lastname: Ou
authors.forename: C Bruce
authors.initials: CB
authors.lastname: Verchere
authors.forename: Alice
authors.initials: A
authors.lastname: Mui
authors.forename: Garth L
authors.initials: GL
authors.lastname: Warnock
mesh_terms: D000818:Animals; D000906:Antibodies / Q000378:metabolism / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1 / Q000378:metabolism / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000906:Antibodies; D011993:Recombinant Fusion Proteins; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1; C475824:Vtcn1 protein, mouse; D051058:Oncogene Protein v-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases