Abstract
The relative importance of the cytokine milieu versus cytolytic T lymphocyte-associated antigen 4 (CTLA-4) and T cell receptor signal strength on T cell differentiation remains unclear. Here we have generated mice deficient for signal transducer and activator of transcription 6 (STAT6) and CTLA-4 to determine the role of CTLA-4 in cytokine-driven T cell differentiation. CTLA-4-deficient T cells bypass the need for STAT6 in the differentiation of T helper type 2 (T(H)2) cells. T(H)2 differentiation of cells deficient for both STAT6 and CTLA-4 is accompanied by induction of GATA-3 and the migration of T(H)2 cells to peripheral tissues. CTLA-4 deficiency also affects the balance of the nuclear factors NFATc1 and NFATc2, and enhances activation of NF-kappaB. These results suggest that CTLA-4 has a critical role in T cell differentiation and that STAT6-dependent T(H)2 lineage commitment and stabilization can be bypassed by increasing the strength of signaling through the T cell receptor.
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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Abatacept
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Animals
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Antigens, CD
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Antigens, Differentiation / genetics
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Antigens, Differentiation / metabolism*
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CTLA-4 Antigen
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Cell Differentiation
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Cell Movement
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Cytokines / metabolism*
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / metabolism
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GATA3 Transcription Factor
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Immunoconjugates*
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Immunoglobulin Class Switching
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Mice
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Mice, Inbred BALB C
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Mice, Inbred NOD
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Mice, Knockout
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NF-kappa B / metabolism
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NFATC Transcription Factors
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Nuclear Proteins*
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STAT6 Transcription Factor
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Signal Transduction
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Th2 Cells / cytology
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Th2 Cells / immunology*
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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 / immunology
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Transcription Factors / metabolism
Substances
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Antigens, CD
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Antigens, Differentiation
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CTLA-4 Antigen
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Ctla4 protein, mouse
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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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Immunoconjugates
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NF-kappa B
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NFATC Transcription Factors
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Nfatc1 protein, mouse
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Nfatc2 protein, mouse
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Nuclear Proteins
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STAT6 Transcription Factor
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Stat6 protein, mouse
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Trans-Activators
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Transcription Factors
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Abatacept