Abstract
ICOS is the third member of the CD28 family molecules and plays a critical role in many T cell-dependent immune responses. Although accumulated data suggest that ICOS costimulatory signals play an important role in Th2-mediated immune responses, the molecular basis for this selective differentiation mechanism is largely unknown. To clarify this mechanism, we used DO11.10 TCR transgenic ICOS-/- mice and evaluated the nature of ICOS costimulatory signals during the process of Ag-specific activation and differentiation of naive CD4+ T cells. Results obtained from these experiments demonstrated that Ag stimulation of naive CD4+ T cells in the absence of an ICOS signal resulted in impaired Th2 development. Unlike previous reports, we found that primary IL-4 production by these T cells was intact and that IL-4R sensitivity of these T cells was reduced as evidenced by a profound defect in IL-4-induced Stat6 phosphorylation and the early induction of GATA-3. The fact that ICOS ligation of wild-type T cells significantly enhanced IL-4-induced Stat6 phosphorylation and primary GATA-3 induction, but not IL-4 transcription, of naive CD4+ T cells was consistent with the results obtained from ICOS-/- T cell experiments. These observations led us to propose that the predominant effect of ICOS-mediated costimulation on Th2 differentiation is achieved by the enhancement of IL-4R-mediated signaling.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adjuvants, Immunologic / genetics
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Adjuvants, Immunologic / physiology*
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Animals
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Antigen Presentation / genetics
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Antigens, Differentiation, T-Lymphocyte / genetics
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Antigens, Differentiation, T-Lymphocyte / physiology*
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CD4-Positive T-Lymphocytes / cytology
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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Cell Differentiation / genetics
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Cell Differentiation / immunology*
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Cells, Cultured
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / physiology
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GATA3 Transcription Factor
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Inducible T-Cell Co-Stimulator Protein
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Interleukin-4 / biosynthesis
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Lymphocyte Activation* / genetics
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Receptors, Interleukin-4 / antagonists & inhibitors
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Receptors, Interleukin-4 / genetics
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Receptors, Interleukin-4 / physiology*
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Repressor Proteins / physiology
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Resting Phase, Cell Cycle / immunology
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STAT6 Transcription Factor
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Signal Transduction / genetics
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Signal Transduction / immunology*
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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Th2 Cells / cytology*
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Th2 Cells / immunology*
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Th2 Cells / metabolism
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Trans-Activators / biosynthesis
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Trans-Activators / metabolism
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Trans-Activators / physiology
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Transcription Factors / physiology
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Transcription, Genetic / immunology
Substances
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Adjuvants, Immunologic
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Antigens, Differentiation, T-Lymphocyte
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DNA-Binding Proteins
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GATA3 Transcription Factor
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Gata3 protein, mouse
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Icos protein, mouse
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Inducible T-Cell Co-Stimulator Protein
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Receptors, Interleukin-4
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Repressor Proteins
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STAT6 Transcription Factor
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Socs3 protein, mouse
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Stat6 protein, mouse
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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Trans-Activators
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Transcription Factors
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Interleukin-4