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By
From the Department of Immunology, The Scripps Research Institute, La Jolla, California 92037
There is little known about the regulation of gene expression during TCR-mediated differentiation of immature CD4+8+ (double positive) thymocytes into mature T cells. Using the DPK CD4+8+thymocyte precursor cell line, we demonstrate that the early growth response-1 gene
(Erg-1), encoding a zinc finger transcription factor, is rapidly upregulated after TCR stimulation. We also report that Egr-1 is expressed by a subset of normal double positive thymocytes
in the thymic cortex, as well by a majority of medullary single positive thymocytes. Expression
of Egr-1 is dramatically reduced in the thymus of major histocompatibility complex knockout mice, but can be induced by anti-CD3 antibody stimulation of isolated thymocytes from these
animals. These and other data suggest that high level expression of Egr-1 in the thymus is a
consequence of selection. A similar pattern of expression is found for family members Egr-2
and Egr-3. Using the DPK cell line, we also demonstrate that expression of Egr-1, 2, and 3 is
dependent upon ras activation, as is the initiation of differentiation to a single positive cell. In
contrast, the calcineurin inhibitor cyclosporin A, which inhibits DPK cell differentiation as
well as positive selection, inhibits expression of Egr-2 and Egr-3, but not Egr-1. The identification of the Egr family in this context represents the first report of a link between the two
known signaling pathways involved in positive selection and downstream transcriptional regulators.
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