Abstract
cAMP response element binding protein (CREB) is a critical regulator of diverse stimulus-dependent transcriptional events. Following TCR stimulation, CREB is rapidly induced in CD4+ Th cell precursors, but not in effector Th cells. However, its role in mature T cell function is incompletely defined. Transgenic mice expressing a CREB dominant-negative (dn) mutation in the T cell lineage exhibited normal T cell development in the thymus, normal T cell homeostasis in the periphery, and normal T cell clonal expansion following Ag challenge. However, this mutation caused selective inhibition of Th cell function in vitro and in vivo, and increased susceptibility of Th cells to activation-induced cell death. Th cells expressing the CREB-dn mutation contained reduced levels of the inhibitor of programmed cell death, BCL-2; overexpression of BCL-2 in transgenic mice reversed both susceptibility to activation-induced cell death in CREB-dn T cells and the defect in effector cytokine production. Thus, CREB plays a critical role in Th cell function and development of Th cell-mediated adaptive immune responses, at least in part, by inhibiting stimulus-dependent cell death.
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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Alanine / genetics
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Amino Acid Substitution / genetics
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Amino Acid Substitution / immunology
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Animals
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Cell Death / immunology
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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Cell Division / genetics
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Cell Division / immunology
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Cyclic AMP Response Element-Binding Protein / biosynthesis
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Cyclic AMP Response Element-Binding Protein / genetics*
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Cyclic AMP Response Element-Binding Protein / metabolism
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Cyclic AMP Response Element-Binding Protein / physiology
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Homeostasis / immunology
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Interleukin-2 / biosynthesis
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Interphase / genetics
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Interphase / immunology
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Lymphocyte Activation / genetics
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Point Mutation*
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Proto-Oncogene Proteins c-bcl-2 / physiology*
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Receptors, Antigen, T-Cell / immunology
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Serine / genetics
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T-Lymphocytes, Helper-Inducer / cytology
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T-Lymphocytes, Helper-Inducer / immunology*
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T-Lymphocytes, Helper-Inducer / metabolism*
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Thymus Gland / cytology
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Thymus Gland / immunology
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Thymus Gland / metabolism
Substances
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Cyclic AMP Response Element-Binding Protein
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Interleukin-2
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Proto-Oncogene Proteins c-bcl-2
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Receptors, Antigen, T-Cell
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Serine
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Alanine