Abstract
CD4 T cell differentiation is a complex process affected by many transcription factors interacting in a tightly regulated manner. We have previously shown that CIITA-deficient mouse Th1 cells expressed Th2-type cytokines, while IFN-gamma expression was normal. In this study, we show that CIITA-deficient Th1 cells contain three distinct populations: cells secreting IL-4 alone, IFN-gamma alone, and both IL-4 and IFN-gamma together. This novel phenotype is stable over multiple rounds of stimulation in the presence of Th1-inducing factors. CIITA-deficient Th1 cells require TCR-mediated signaling to express Th2 cytokines, and this occurs with similar kinetics as wild-type Th2 cells. Both GATA-3 and IL-4 appear to be required for CIITA-deficient Th1 cells to express Th2-type cytokines. Interestingly, however, CIITA-deficient Th1 cells can produce IL-4 in the absence of exogenous IL-4. Introducing either CIITA or antisense GATA-3 during Th1 differentiation partially reduces Th2-type cytokine expression. With the exception of Th2-type cytokine expression, Th1 differentiation occurs normally in the absence of CIITA, as measured by expression of T-bet, IL-12Rbeta2, IL-18Ralpha, and IFN-gamma. Therefore, CIITA plays a key role to repress Th2-type cytokine expression as naive CD4 T cells differentiate toward the Th1 lineage.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cell Differentiation / genetics
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Cell Differentiation / immunology*
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Cell Lineage / genetics
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Cell Lineage / immunology
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Cells, Cultured
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Cytokines / antagonists & inhibitors
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Cytokines / biosynthesis
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DNA-Binding Proteins / biosynthesis
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GATA3 Transcription Factor
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Histocompatibility Antigens Class II / genetics*
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Immunophenotyping
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Interferon-gamma / biosynthesis
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Interleukin-13 / biosynthesis
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Interleukin-4 / biosynthesis
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Interleukin-4 / physiology
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Interleukin-5 / biosynthesis
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Lymphocyte Activation / genetics
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Lymphocyte Activation / immunology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Nuclear Proteins / deficiency*
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Nuclear Proteins / genetics*
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Nuclear Proteins / physiology
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Signal Transduction / genetics
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Signal Transduction / immunology*
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Th1 Cells / cytology*
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Th1 Cells / immunology*
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Th1 Cells / metabolism
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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 / deficiency*
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Trans-Activators / genetics*
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Trans-Activators / physiology
Substances
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Cytokines
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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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Histocompatibility Antigens Class II
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Interleukin-13
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Interleukin-5
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MHC class II transactivator protein
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Nuclear Proteins
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Trans-Activators
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Interleukin-4
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Interferon-gamma