Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 199, Issue 8, Pages 1089-1099Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20040051
Keywords
HMG box; T cell development; TCR signaling; gene regulation; Runx
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Funding
- NIAID NIH HHS [AI44110, AI054977, R01 AI054977] Funding Source: Medline
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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 tip-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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