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.
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.
Okamoto
Naokazu
N
Department of Biological Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, Noda, Chiba, Japan.
Tezuka
Katsunari
K
Kato
Masako
M
Abe
Ryo
R
Tsuji
Takashi
T
D015703:Antigens, CD / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis*; D018106:CD28 Antigens / Q000096:biosynthesis*; D017252:CD3 Complex / Q000096:biosynthesis; D002455:Cell Division; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D060889:Inducible T-Cell Co-Stimulator Protein; D016753:Interleukin-10 / Q000096:biosynthesis*; D007376:Interleukin-2 / Q000096:biosynthesis / Q000378:metabolism; D037181:Lectins, C-Type; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D020935:MAP Kinase Signaling System; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism*; D020032:Tyrphostins / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D018106:CD28 Antigens; D017252:CD3 Complex; D016207:Cytokines; D004791:Enzyme Inhibitors; D060889:Inducible T-Cell Co-Stimulator Protein; D016753:Interleukin-10; D007376:Interleukin-2; D037181:Lectins, C-Type; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D015375:Receptors, Interleukin-2; D020032:Tyrphostins; D048051:p38 Mitogen-Activated Protein Kinases; D000099192:CD69 Antigens; C556692:ICOS protein, human; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C482128:MAP2K2 protein, human; C482125:MAP2K1 protein, human