Opposing regulation of T cell function by Egr-1/NAB2 and Egr-2/Egr-3

• Published in: European journal of immunology Vol. 38; no. 2; pp. 528 - 536
• Main Authors: Collins, Sam, Lutz, Michael A, Zarek, Paul E, Anders, Robert A, Kersh, Gilbert J, Powell, Jonathan D
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley-VCH Verlag 01.02.2008; WILEY‐VCH Verlag
• Subjects: Activation; Animals; Early Growth Response Protein 1 - antagonists & inhibitors; Early Growth Response Protein 1 - biosynthesis; Early Growth Response Protein 1 - genetics; Early Growth Response Protein 1 - physiology; Early Growth Response Protein 2 - biosynthesis; Early Growth Response Protein 2 - deficiency; Early Growth Response Protein 2 - genetics; Early Growth Response Protein 2 - physiology; Early Growth Response Protein 3 - biosynthesis; Early Growth Response Protein 3 - deficiency; Early Growth Response Protein 3 - genetics; Early Growth Response Protein 3 - physiology; EGR; Gene Expression Regulation - immunology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; NAB2; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - genetics; Neoplasm Proteins - physiology; Receptors, Antigen, T-Cell - physiology; Repressor Proteins - antagonists & inhibitors; Repressor Proteins - biosynthesis; Repressor Proteins - genetics; Repressor Proteins - physiology; T cells; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Tolerance
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.200737157

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.