Egr-2 and Egr-3 are negative regulators of T cell activation
Meredith Safford, Samuel Collins, Michael A. Lutz, Amy Allen, Ching-Tai Huang, Jeanne Kowalski, Amanda Blackford, Maureen R. Horton, Charles Drake, Ronald H. Schwartz and Jonathan D. Powell. Nature Immunology. 6:472 Ð 480, (2005) Published online 17 April 2005.
T cell anergy is defined as a nonresponsiveness to activation in the absence of costimulatory molecules. The mechanism by which specific molecules induce T cell anergy remains unclear. Egr2 and Egr3 are differentially expressed during both T and B cell anergy. However, the precise functions of Egr2 and Egr3 have not been addressed.
To identify the genes and pathways that promote T cell anergy, five conditions were used to stimulate T cells, and T cell anergy was assessed. Expression profiles from stimulated T cells were analyzed by the Affymetrix7 GeneChip7 U74A, B and C arrays. The functional relationships of the candidate genes were explored using the IPA application.
One hundred fifty-six unique genes were identified in stimulated T cells and the majority of these encoded transcription factors. As displayed in Supplementary Figure 1 of this paper, three potential networks were recognized by the IPA application and the Ingenuity Pathways Knowledge Base. Transcription factor Egr2 is prominent in one of the networks.
The expression of Egr2 and Egr3 was further analyzed from microarray data. Both Egr2 and Egr3 expression was upregulated by TCR activation and inhibited by CsA. CsA corresponded to inhibition of IL2 production – that is, anergy induction. Real time PCR, immunoblotting, in vivo animal model testing, and transgenic model testing validated these results. This study demonstrates that the transcription factors Egr2 and Egr3 induce T cell anergy by upregulating a set of T cell inhibitory genes or other mediators. |
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