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¹ Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037
² Molecular Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan
³ Division of Molecular Cardiovascular Biology, Children's Hospital Medical Center, Cincinnati, OH 45229

Address correspondence to Jonathan Kaye, Dept. of Immunology IMM-8, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 784-9495; Fax: (858) 784-8805; email: jkaye{at}scripps.edu

T cell development is dependent on the integration of multiple signaling pathways, although few links between signaling cascades and downstream nuclear factors that play a role in thymocyte differentiation have been identified. We show here that expression of the HMG box protein TOX is sufficient to induce changes in coreceptor gene expression associated with ß-selection, including CD8 gene demethylation. TOX expression is also sufficient to initiate positive selection to the CD8 lineage in the absence of MHC–TCR interactions. TOX-mediated positive selection is associated with up-regulation of Runx3, implicating CD4 silencing in the process. Interestingly, a strong T cell receptor–mediated signal can modify this cell fate. We further demonstrate that up-regulation of TOX in double positive thymocytes is calcineurin dependent, linking this critical signaling pathway to nuclear changes during positive selection.

Key Words: HMG box • T cell development • TCR signaling • gene regulation • Runx

Abbreviations used in this paper: CD8ISP, CD4^–CD8⁺ immature single positive thymocyte; Cn, calcineurin; DN, CD4^–8^– double negative thymocyte; DP, CD4⁺8⁺ double positive thymocyte; HMG, high mobility group; MAPK, mitogen-activated protein kinase; SP, CD4⁺8^– or CD4^–8⁺ single positive thymocyte; Tg, transgenic; TOX, thymocyte selection-associated HMG box protein.

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This article has been cited by other articles:

• Aliahmad, P., Kaye, J. (2008). Development of all CD4 T lineages requires nuclear factor TOX. JEM 205: 245-256 [Abstract] [Full Text]  
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