Abstract
The activation of resting T cells for the acquisition of various functions depends on whether CD28 costimulatory signals are provided upon T cell receptor stimulation. Here, we investigated how CD28 costimulation functions to allow TCR-triggered resting T cells to acquire IL-12 responsiveness. When T cells are stimulated with low doses of anti-CD3 mAb, CD28 costimulation was required for the optimal levels of IL-12 receptor (IL-12R) expression. However, stimulation of T cells with high doses of anti-CD3 alone induced comparable levels of IL-12R expression to those induced upon CD28 costimulation. Nevertheless, there was a substantial difference in IL-12 responsiveness between these two groups of T cells: compared to anti-CD28-costimulated T cells, T cells that were not costimulated with anti-CD28 exhibited decreased levels of Janus kinases (JAK) JAK2/TYK2 and STAT4 phosphorylation and IFN-y production following IL-12 stimulation. Importantly, STAT6 phosphorylation following IL-4 stimulation was not decreased in anti-CD28-uncostimulated T cells. These resutls indicate that CD28 costimulation not only contributes to up-regulating IL-12R expression but is also required to render JAKs/STAT4 responsive to IL-12 stimulation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blotting, Western
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CD28 Antigens / metabolism*
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Cells, Cultured
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DNA-Binding Proteins / metabolism*
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Enzyme Activation / drug effects
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Flow Cytometry
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Interferon-gamma / metabolism
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Interleukin-12 / pharmacology*
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Interleukin-4 / pharmacology
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JNK Mitogen-Activated Protein Kinases
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Lymphocyte Activation / drug effects
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Mice
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Mice, Inbred C57BL
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Mitogen-Activated Protein Kinases / metabolism*
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Phosphorylation / drug effects
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptors, Antigen, T-Cell / metabolism*
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Receptors, Interleukin / metabolism*
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Receptors, Interleukin-12
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STAT4 Transcription Factor
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STAT6 Transcription Factor
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Signal Transduction / drug effects
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T-Lymphocytes / cytology
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T-Lymphocytes / drug effects*
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T-Lymphocytes / enzymology
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T-Lymphocytes / metabolism
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Trans-Activators / metabolism*
Substances
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CD28 Antigens
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DNA-Binding Proteins
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RNA, Messenger
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Receptors, Antigen, T-Cell
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Receptors, Interleukin
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Receptors, Interleukin-12
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STAT4 Transcription Factor
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STAT6 Transcription Factor
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Stat4 protein, mouse
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Stat6 protein, mouse
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Trans-Activators
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Interleukin-12
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Interleukin-4
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Interferon-gamma
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases