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-Selection Checkpoint1
* Division of Basic Sciences, Immunobiology Working Group, Fox Chase Cancer Center, Philadelphia, PA 19111;
Department of Immunology, University of Toronto, Sunnybrook Research Institute, Toronto, Ontario, Canada;
Cancer Biology and Genetics Program, Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021;
Division of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan; and
¶ Department of Pharmacology, Loyola University Chicago, Maywood, IL 60153
Development of immature T cell precursors beyond the 
-selection checkpoint is regulated by signals transduced by the pre-TCR complex. The pre-TCR-induced differentiation program is orchestrated by a network of transcription factors that serve to integrate this signaling information. Among these transcription factors are those of the early growth response (Egr) and NF-AT families. In this study, we demonstrate that Egr1 and NF-ATc1 act together to promote development of T cell precursors beyond the -selection checkpoint to the CD8 immature single-positive and CD4+CD8+ double-positive stages. Moreover, we find that Egr1 and NF-AT cooperatively induce the expression of inhibitor of DNA binding 3 (Id3), a regulatory factor known to play an important role in positive selection of thymocytes, but not previously demonstrated to be required for -selection. Importantly, we show in this study that Id3 deficiency abrogates the ability of ectopically expressed Egr1 to promote traversal of the -selection checkpoint. Id3 is presumably essential for traversal of the -selection checkpoint in this context because of the inability of other inhibitor of DNA binding family members to compensate, since transgenic Egr1 does not induce expression of inhibitor of DNA binding 1 (Id1) or 2 (Id2). Taken together, these data demonstrate that Id3 is a cooperatively induced target that is important for Egr-mediated promotion of development beyond the -selection checkpoint. Moreover, these data indicate that the ERK and calcium signaling pathways may converge during -selection through the concerted action of Egr1 and NF-ATc1, respectively.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants CA73656, CA87407, and CA100144; National Institutes of Health Core Grant P01CA06927; Center Grant P30-DK-50306; and an appropriation from the Commonwealth of Pennsylvania.
2 Address correspondence and reprint requests to Dr. David L. Wiest, Fox Chase Cancer Center, Division of Basic Sciences, Immunobiology Working Group, R390, 333 Cottman Avenue, Philadelphia, PA 19111. E-mail address: DL_Wiest{at}fccc.edu
3 Abbreviations used in this paper: DN, double negative; CsA, cyclosporin A; DBD, DNA-binding domain; DP, double positive; Egr, early growth response; HLH, helix-loop-helix; HPC, hemopoietic precursor cell; Id1, inhibitor of DNA binding 1; Id2, inhibitor of DNA binding 2; Id3, inhibitor of DNA binding 3; IRES, internal ribosomal entry site; ISP, immature single positive; Tg, transgenic; YFP, yellow fluorescent protein.
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