Abstract
During development, progenitor thymocytes differentiate into either CD4 or CD8 T cells, and this fate decision depends on the specificity of the T cell antigen receptor (TCR) for MHC class II or class I molecules. Based on the mechanisms of fate specification known for simple metazoan organisms, we sought to determine whether the extracellular signal-related kinases (ERKs) play a role in T cell differentiation and lineage commitment. Using a dominant gain-of-function mutant of the erk2 gene, we show that differentiation into the CD4 lineage is favored. We also show that, conversely, the addition of a pharmacological inhibitor of the ERK pathway favors differentiation into the CD8 lineage. We present a quantitative selection model that incorporates these results as well as those of recent reports on the role of Notch in T cell lineage specification.
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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Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
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Calcium-Calmodulin-Dependent Protein Kinases / physiology*
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Cell Differentiation
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Cells, Cultured
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Enzyme Activation / drug effects
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Enzyme Inhibitors / pharmacology
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Female
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Flavonoids / pharmacology
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Lymph Nodes / cytology
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Lymphocyte Activation
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Male
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Membrane Proteins / physiology
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Mice
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Mice, Transgenic
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Mitogen-Activated Protein Kinase 1
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Receptors, Antigen, T-Cell, alpha-beta / genetics
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Receptors, Notch
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Signal Transduction / drug effects
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T-Lymphocyte Subsets / cytology
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T-Lymphocytes / cytology*
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T-Lymphocytes / enzymology
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Thymus Gland / cytology*
Substances
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Enzyme Inhibitors
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Flavonoids
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Membrane Proteins
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Receptors, Antigen, T-Cell, alpha-beta
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Receptors, Notch
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Calcium-Calmodulin-Dependent Protein Kinases
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Mitogen-Activated Protein Kinase 1
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one