The Journal of Experimental Medicine
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Published online 12 April 2004 doi:10.1084/jem.20040051
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 8, 1089-1099
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TOX Provides a Link Between Calcineurin Activation and CD8 Lineage Commitment

Parinaz Aliahmad1, Emmett O'Flaherty1, Peggy Han1, Olivia D. Goularte1, Beverley Wilkinson1, Masanobu Satake2, Jeffery D. Molkentin3, and Jonathan Kaye1

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

P. Aliahmad and E. O'Flaherty contributed equally to this work.

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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