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J Exp Med. 2004 Apr 19;199(8):1089-99. Epub 2004 Apr 12.

TOX provides a link between calcineurin activation and CD8 lineage commitment.

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  • 1Department of Immunology IMM-8, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, USA.


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 beta-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.

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