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Early growth response 2 regulates the survival of thymocytes during positive selection
Author(s) -
Lawson Victoria J.,
Weston Kathleen,
Maurice Diane
Publication year - 2010
Publication title -
european journal of immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.272
H-Index - 201
eISSN - 1521-4141
pISSN - 0014-2980
DOI - 10.1002/eji.200939567
Subject(s) - biology , downregulation and upregulation , suppressor of cytokine signaling 1 , stat5 , signal transduction , microbiology and biotechnology , transcription factor , cancer research , socs2 , suppressor , genetics , gene
Abstract The early growth response (Egr) transcription factor family regulates multiple steps during T‐cell development. We examine here the role played by Egr2 in positive selection. In double‐positive cells, Egr2 is upregulated immediately following TCR ligation, and its expression requires both the MAPK and calcineurin signaling pathways. Inducible transgenic and knockout mice were generated to cause gain‐ or loss‐of‐function of Egr2 in double‐positive cells, and had reciprocal effects; more mature single‐positive cells were made when Egr2 was overexpressed, and fewer when Egr2 was absent. These defects were associated with changes in the survival of positively selected cells rather than perturbation of positive selection or immediate post‐selection signaling. The survival function of Egr2 at least partly depends upon its ability to activate the cytokine‐mediated survival pathway, likely through negative regulation of both the IL‐7R and suppressor of cytokine signaling 1 (Socs1), the molecular switch whose downregulation normally results in restored responsiveness to cytokine signaling following selection. While gain of Egr2 caused a decrease in Socs1 mRNA, loss of Egr2 resulted in downregulation of IL‐7R, upregulation of Socs1, and inhibition of Stat5 phosphorylation and IL‐7‐mediated survival post‐selection. Therefore, expression of Egr2 following positive selection links the initial TCR signaling event to subsequent survival of signaled cells.