The differentiation of CD4 CD8 double positive (DP) thymocytes requires the irreversible
choice between two alternative lineages, distinguished by the mutually exclusive expression of
either CD4 or CD8. Differentiating DP cells transiently down-regulate both CD4 and CD8,
and this has complicated the debate whether the mechanism of CD4/CD8 lineage choice is instructive, stochastic/selective, or more complex in nature. Using fluorescence in situ hybridization,
we show that the stable silencing of coreceptor loci, and ultimately lineage choice, is predicted
by the spatial repositioning of coreceptor alleles to centromeric heterochromatin domains.
These data provide evidence that lineage-specific developmental programs are established early
during the transition from the DP to the single positive stage.