Abstract
To delineate the molecular mechanisms regulating Th2 cell differentiation, CD28-mediated generation of Th2 effectors was analyzed. In the absence of TCR ligation CD28 stimulation induced Th2 differentiation of memory but not of naive CD4(+) T cells, whereas costimulation via CD28 and the TCR enhanced Th2 differentiation from naive T cells but suppressed it from memory T cells. Stimulation of T cells via the CD28 pathway, therefore, provided critical signals facilitating Th2 cell differentiation. By comparing the responses to CD28 stimulation in memory and naive T cells and by using specific inhibitors, signaling pathways were defined that contributed to Th2 differentiation. CD28-induced Th2 differentiation required IL-4 stimulation and the activation of the mitogen-activated protein kinases p38 and extracellular signal-regulated kinases 1/2. CD28 engagement directly initiated IL-4 gene transcription in memory T cells and induced activation of phosphatidylinositol 3-kinase, p38, and c-Jun NH(2)-terminal kinase/stress-activated protein kinase pathways. Extracellular signal-regulated kinase phosphorylation that was necessary for Th2 differentiation, however, required stimulation by IL-2. These results indicate that optimal TCR-independent generation of Th2 effectors requires coordinate signaling via the CD28 and IL-2 pathways. TCR-independent generation of Th2 effectors might provide a mechanism to control Th1-dominated cellular inflammation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Antibodies, Monoclonal / pharmacology
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Antigens, CD / metabolism
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Antigens, CD / physiology
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B7-1 Antigen / metabolism
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B7-1 Antigen / physiology
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B7-2 Antigen
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CD28 Antigens / immunology
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CD28 Antigens / metabolism
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CD28 Antigens / physiology*
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CD4-Positive T-Lymphocytes / cytology
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CD4-Positive T-Lymphocytes / enzymology
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CD4-Positive T-Lymphocytes / immunology
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Cell Differentiation / immunology
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Cells, Cultured
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Drug Synergism
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Enzyme Activation / immunology
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Fetal Blood
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Gene Expression Regulation / immunology*
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Humans
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Immunologic Memory / genetics
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Interleukin-4 / biosynthesis*
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Interleukin-4 / genetics*
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Interleukin-4 / physiology
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Interphase / genetics
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Interphase / immunology
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Jurkat Cells
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Ligands
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Membrane Glycoproteins / metabolism
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Membrane Glycoproteins / physiology
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Mitogen-Activated Protein Kinases / metabolism*
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Mitogen-Activated Protein Kinases / physiology
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Phosphorylation
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Signal Transduction / immunology
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T-Lymphocyte Subsets / cytology
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism
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Th2 Cells / cytology*
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Th2 Cells / enzymology*
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Th2 Cells / immunology
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Transcription, Genetic / immunology
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Tyrosine / metabolism
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p38 Mitogen-Activated Protein Kinases
Substances
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Antibodies, Monoclonal
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Antigens, CD
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B7-1 Antigen
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B7-2 Antigen
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CD28 Antigens
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CD86 protein, human
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Ligands
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Membrane Glycoproteins
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Proto-Oncogene Proteins
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Interleukin-4
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Tyrosine
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases