Abstract
TCR-induced NF-AT activation leads to the up-regulation of multiple genes involved in T cell anergy. Since NF-AT is also involved in T cell activation, we have endeavored to dissect TCR-induced activating and inhibitory genetic programs. This approach revealed roles for the early growth response (Egr) family of transcription factors and the Egr coactivator/corepressor NGFI-A-binding protein (NAB)2 in regulating T cell function. TCR-induced Egr-1 and NAB2 enhance T cell function, while Egr-2 and Egr-3 inhibit T cell function. In this report, we demonstrate that Egr-2 and Egr-3 are induced by NF-AT in the absence of AP-1, while Egr-1 and NAB2 both require AP-1-mediated transcription. Our data suggest that Egr-3 is upstream of Egr-2, and that mechanistically Egr-2 and Egr-3 suppress Egr-1 and NAB2 expression. Functionally, T cells from Egr-2 and Egr-3 null mice are hyperresponsive while T cells from Egr-3 transgenic, overexpressing mice are hyporesponsive. Furthermore, an in vivo model of autoimmune pneumonitis reveals that T cells from Egr-3 null mice hasten death while Egr-3-overexpressing T cells cause less disease. Overall, our data suggest that just as the Egr/NAB network of genes control cell fate in other systems, TCR-induced Egr-1, 2, 3 and NAB2 control the fate of antigen recognition in T cells.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Early Growth Response Protein 1 / antagonists & inhibitors
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Early Growth Response Protein 1 / biosynthesis
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Early Growth Response Protein 1 / genetics
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Early Growth Response Protein 1 / physiology*
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Early Growth Response Protein 2 / biosynthesis
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Early Growth Response Protein 2 / deficiency
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Early Growth Response Protein 2 / genetics
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Early Growth Response Protein 2 / physiology*
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Early Growth Response Protein 3 / biosynthesis
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Early Growth Response Protein 3 / deficiency
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Early Growth Response Protein 3 / genetics
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Early Growth Response Protein 3 / physiology*
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Gene Expression Regulation / immunology
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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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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Receptors, Antigen, T-Cell / physiology
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Repressor Proteins / antagonists & inhibitors
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Repressor Proteins / biosynthesis
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Repressor Proteins / genetics
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Repressor Proteins / physiology*
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T-Lymphocytes / immunology*
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T-Lymphocytes / metabolism
Substances
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Early Growth Response Protein 1
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Early Growth Response Protein 2
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Egr1 protein, mouse
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Egr2 protein, mouse
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Egr3 protein, mouse
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Nab2 protein, mouse
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Neoplasm Proteins
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Receptors, Antigen, T-Cell
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Repressor Proteins
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Early Growth Response Protein 3