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Epigenetic silencing of CD4 in T cells committed to the cytotoxic lineage

Abstract

The process of thymocyte development culminates in the maturation of helper (CD4+) and cytotoxic (CD8+) T cells from their common precursors, the CD4+CD8+ double-positive cells1,2. A crucial step during lineage specification is the termination of expression of either the CD4 or the CD8 coreceptor3,4. A silencer element within the first intron of the CD4 gene is sufficient for CD4 transcriptional repression in cells of the cytotoxic lineage, as well as in thymocytes at earlier stages of differentiation5,6. Here we show that the function of the CD4 silencer is required only at distinct stages of development. Its deletion before the initiation of lineage specification resulted in CD4 derepression throughout thymocyte differentiation. By contrast, once cells committed to the cytotoxic CD8+ lineage, the CD4 locus remained silent through subsequent mitoses, even when the silencer element was excised. The epigenetic inheritance of the silenced CD4 locus was not affected by the inhibition of DNA methylation or histone deacetylation, and may thus involve other mechanisms that ensure a stable state of gene expression.

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Figure 1: Conditional ablation of the CD4 silencer.
Figure 2: Germline deletion of the CD4 silencer results in derepression of CD4 in thymocytes and cytotonic T cells.
Figure 3: Silencer-independent maintenance of CD4 repression in mature T cells.
Figure 4: Sustained repression of CD4 expression in CD8+ T cells after inhibition of DNA methylation and histone deacetylation.

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Acknowledgements

We thank I. Riviere for her participation in the early phase of this project, J. Hirst for cell sorting, H. Singh for the MSCV–EGFP vector and H. Gu and D.S. Kwon for critical reading of the manuscript. Y.-R.Z. was the recipient of a postdoctoral fellowship from the Irvington Institute and D.R.L. is an Investigator of the Howard Hughes Medical Institute.

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Correspondence to Yong-Rui Zou or Dan R. Littman.

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Zou, YR., Sunshine, MJ., Taniuchi, I. et al. Epigenetic silencing of CD4 in T cells committed to the cytotoxic lineage. Nat Genet 29, 332–336 (2001). https://doi.org/10.1038/ng750

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