Induction of the early growth response (Egr) family of transcription factors during thymic selection.
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.
Shao
H
H
Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA.
Kono
D H
DH
Chen
L Y
LY
Rubin
E M
EM
Kaye
J
J
D000818:Animals; D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D051766:Early Growth Response Protein 1; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D017874:Immediate-Early Proteins; D008285:Major Histocompatibility Complex / Q000276:immunology; D051379:Mice; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D017874:Immediate-Early Proteins; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; D016572:Cyclosporine; D016283:Proto-Oncogene Proteins p21(ras)