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TOX: an HMG box protein implicated in the regulation of thymocyte selection

Abstract

In the thymus, pre-T cell receptor (pre-TCR)–mediated signaling and then TCR-mediated signaling initiate changes in gene expression that result in the maturation of CD4 and CD8 lineage T cells from common precursors. Using gene chip technology, we isolated a murine gene, designated Tox, that encodes a member of the HMG (high-mobility group) box family of DNA-binding proteins. TOX expression is up-regulated by both pre-TCR and TCR activation of immature thymocytes but not by TCR activation of mature naïve T cells. Transgenic mice that express TOX show expanded CD8+ and reduced CD4+ single positive thymocyte subpopulations. We present evidence here that this phenotype results from a perturbation in lineage commitment due to reduced sensitivity to TCR-mediated signaling. This molecular marker of thymic selection events may therefore play a role in establishing the activation threshold of developing T cells and patterning changes in gene expression.

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Figure 1: Nuclear localization of Tox protein is independent of the HMG box.
Figure 2: Expression pattern of TOX.
Figure 3: TOX expression in DN thymocytes and peripheral lymphocytes
Figure 4: Altered thymocyte subsets in TOX-Tg mice.
Figure 5: Alteration of TCR repertoire in TOX-Tg mice.
Figure 6: Reduced expression of CD5 in TOX-Tg thymocyte subsets.
Figure 7: Alteration in lineage commitment in genetically modified mice that were expressing the TOX transgene.

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Acknowledgements

We thank A. Feeney and E. O'Flaherty for critical review of this manuscript; S. Head for help with microarray analysis; C. Surh and J. Sprent for mice; D. Witherden for providing helpful technical advice; and R. Ulevitch and T. Chao for their help with fluorescence microscopy. Supported by a grant from the National Institutes of Health (AI44110) (to J. K.).

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Correspondence to Jonathan Kaye.

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Web Figure 1.

Nucleotide sequence and predicted amino acid sequence of TOX. The complete coding sequence of a murine TOX cDNA and the predicted amino acid sequence of the TOX protein (TOXp) are shown. A putative bipartite nuclear localization signal is underlined and the HMG box motif is highlighted in gray. Residues that differ between TOX protein and the predicted amino acid sequence encoded by a human brain cDNA, KIAA0808, are also shown. (GIF 128 kb)

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Wilkinson, B., Chen, JF., Han, P. et al. TOX: an HMG box protein implicated in the regulation of thymocyte selection. Nat Immunol 3, 272–280 (2002). https://doi.org/10.1038/ni767

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