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The zinc finger protein cKrox directs CD4 lineage differentiation during intrathymic T cell positive selection

Abstract

The genetic programs directing CD4 or CD8 T cell differentiation in the thymus remain poorly understood. While analyzing gene expression during intrathymic T cell selection, we found that Zfp67, encoding the zinc finger transcription factor cKrox, was upregulated during the differentiation of CD4+ but not CD8+ T cells. Expression of a cKrox transgene impaired CD8 T cell development and caused major histocompatibility complex class I–restricted thymocytes to differentiate into CD4+ T cells with helper properties rather than into cytotoxic CD8+ T cells, as normally found. CD4 lineage differentiation mediated by cKrox required its N-terminal BTB (bric-a-brac, tramtrack, broad complex) domain. These findings identify cKrox as a chief CD4 differentiation factor during positive selection.

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Figure 1: Expression of cKrox is upregulated by intrathymic TCR signaling.
Figure 2: Expression of cKrox is upregulated by intrathymic TCR signaling.
Figure 3: Transgenes encoding cKrox.
Figure 4: Transgenic expression of wild-type cKrox in the thymus impairs CD8 T cell development.
Figure 5: Transgenic expression of cKrox redirects MHC class I–restricted thymocytes into the CD4 lineage.
Figure 6: The cKrox transgene affects functional differentiation.
Figure 7: TCR signaling and cKrox.
Figure 8: The BTB-POZ domain is necessary for cKrox function during lineage differentiation.

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Acknowledgements

We thank J. Ashwell, P. Henkart, S. Sarafova and A. Singer for discussions; L. Tian and K. Wildt for assistance with CD154 expression assays; B. Taylor for flow cytometry; G. Sanchez and L. Stepanian for mouse colony management; D. Kappes and X. He (Fox Chase Cancer Center) for communicating their results before publication; and J. Ashwell and A. Singer for critical reading of the manuscript.

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Correspondence to Rémy Bosselut.

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Supplementary Fig. 1

cKrox does not affect TCR signaling in P14 TCR-cKrox transgenic thymocytes. (PDF 206 kb)

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Sun, G., Liu, X., Mercado, P. et al. The zinc finger protein cKrox directs CD4 lineage differentiation during intrathymic T cell positive selection. Nat Immunol 6, 373–381 (2005). https://doi.org/10.1038/ni1183

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