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

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 cells(1,2). A crucial step during lineage spec ification is the termination of expression of either the CD4 or the CD8 cor eceptor(3,4). A silencer element within the first intron of the CD4 gene is sufficient for CD4 transcriptional repression in cells of the cytotoxic li neage, as well as in thymocytes at earlier stages of differentiation(5,6). Here we show that the function of the CD4 silencer is required only at dist inct stages of development. Its deletion before the initiation of lineage s pecification resulted in CD4 derepression throughout thymocyte differentiat ion. By contrast, once cells committed to the cytotoxic CD8(+) lineage, the CD4 locus remained silent through subsequent mitoses, even when the silenc er element was excised. The epigenetic inheritance of the silenced CD4 locu s was not affected by the inhibition of DNA methylation or histone deacetyl ation, and may thus involve other mechanisms that ensure a stable state of gene expression.