Abstract
Both AILIM/ICOS and CD28 provide positive costimulatory signals for T-cell activation, resulting in proliferation and cytokine production. In this study, we attempted to clarify the key signaling molecules in T-cell proliferation, and also IL-2 and IL-10 production, during T-cell activation by CD3 induced by costimulation with either AILIM/ICOS or CD28. We examined the role of both the PI3-kinase/Akt pathway and MAP kinase family members such as ERK1/2, JNK, and p38 kinase in this process. PI3-kinase and Erk1/2 were shown to potentially regulate primary T-cell activation and subsequent proliferation via both AILIM/ICOS- or CD28-mediated costimulation and the Erk signaling cascade was essential for this proliferation induction and also for IL-2 production. The JAK inhibitor, AG490, inhibited this induction. Our studies indicate that IL-2 is necessary for induction of T-cell proliferation and that the quantities of IL-2 produced by AILIM/ICOS ligation are also sufficient for T-cells to proliferate. In contrast, inhibition of Akt and p38, that are phosphorylated by both AILIM/ICOS and CD28-ligation, could downregulate IL-10 production but not T-cell proliferation. These data raise the interesting possibility that the signaling cascades between T-cell proliferation and IL-10 production are regulated by different molecules in AILIM/ICOS- and CD28-costimulated T-cells.
MeSH terms
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Antigens, CD / biosynthesis
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Antigens, Differentiation, T-Lymphocyte / biosynthesis*
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CD28 Antigens / biosynthesis*
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CD3 Complex / biosynthesis
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Cell Division
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Cytokines / biosynthesis
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Dose-Response Relationship, Drug
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Electrophoresis, Polyacrylamide Gel
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Enzyme Inhibitors / pharmacology
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Flow Cytometry
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Humans
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Immunoblotting
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Inducible T-Cell Co-Stimulator Protein
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Interleukin-10 / biosynthesis*
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Interleukin-2 / biosynthesis
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Interleukin-2 / metabolism
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Lectins, C-Type
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MAP Kinase Kinase 1
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MAP Kinase Kinase 2
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MAP Kinase Signaling System*
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Mitogen-Activated Protein Kinases / metabolism
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Models, Biological
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphorylation
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Protein Serine-Threonine Kinases / metabolism
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Protein-Tyrosine Kinases / metabolism
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Receptors, Interleukin-2 / biosynthesis
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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T-Lymphocytes / metabolism*
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Tyrphostins / pharmacology
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p38 Mitogen-Activated Protein Kinases
Substances
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Antigens, CD
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Antigens, Differentiation, T-Lymphocyte
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CD28 Antigens
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CD3 Complex
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CD69 antigen
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Cytokines
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Enzyme Inhibitors
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ICOS protein, human
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Inducible T-Cell Co-Stimulator Protein
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Interleukin-2
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Lectins, C-Type
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Receptors, Interleukin-2
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Tyrphostins
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alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
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Interleukin-10
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MAP2K2 protein, human
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Protein-Tyrosine Kinases
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Protein Serine-Threonine Kinases
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 1
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MAP Kinase Kinase 2
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MAP2K1 protein, human
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Mitogen-Activated Protein Kinase Kinases