PI3-kinase and MAP-kinase signaling cascades in AILIM/ICOS- and CD28-costimulated T-cells have distinct functions between cell proliferation and IL-10 production

Biochem Biophys Res Commun. 2003 Oct 24;310(3):691-702. doi: 10.1016/j.bbrc.2003.09.065.

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

  • Antigens, CD / biosynthesis
  • Antigens, Differentiation, T-Lymphocyte / biosynthesis*
  • CD28 Antigens / biosynthesis*
  • CD3 Complex / biosynthesis
  • Cell Division
  • Cytokines / biosynthesis
  • Dose-Response Relationship, Drug
  • Electrophoresis, Polyacrylamide Gel
  • Enzyme Inhibitors / pharmacology
  • Flow Cytometry
  • Humans
  • Immunoblotting
  • Inducible T-Cell Co-Stimulator Protein
  • Interleukin-10 / biosynthesis*
  • Interleukin-2 / biosynthesis
  • Interleukin-2 / metabolism
  • Lectins, C-Type
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 2
  • MAP Kinase Signaling System*
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mitogen-Activated Protein Kinases / metabolism
  • Models, Biological
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation
  • Protein Serine-Threonine Kinases / metabolism
  • Protein-Tyrosine Kinases / metabolism
  • Receptors, Interleukin-2 / biosynthesis
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • T-Lymphocytes / metabolism*
  • Tyrphostins / pharmacology
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • CD28 Antigens
  • CD3 Complex
  • CD69 antigen
  • Cytokines
  • Enzyme Inhibitors
  • ICOS protein, human
  • Inducible T-Cell Co-Stimulator Protein
  • Interleukin-2
  • Lectins, C-Type
  • Receptors, Interleukin-2
  • Tyrphostins
  • alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
  • Interleukin-10
  • MAP2K2 protein, human
  • Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 2
  • MAP2K1 protein, human
  • Mitogen-Activated Protein Kinase Kinases