A Matter of Choice

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Science  05 Aug 2005:
Vol. 309, Issue 5736, pp. 853
DOI: 10.1126/science.309.5736.853b

Thymocytes develop into two principal lineages: CD4+ or CD8+ T cells. In arriving at either fate, these cells first pass through a double-positive stage in which both CD4 and CD8 co-receptors are expressed, with one or the other later becoming permanently turned off.

To explain how this is regulated, Sarafova et al. extend their kinetic signaling model in which cell fate is determined by the context of T cell receptor (TCR) signals during the initial CD8 down-regulation that takes place in all double-positive thymocytes. The model predicts that continued signaling in these cells (facilitated through TCR and CD4) would maintain CD4 transcription. However, if signaling were not sustained (as would be the case for TCR signals that depend on CD8 receptors), then CD4 expression would stop and CD8 transcription would resume. To test this, thymocytes from CD4-deficient mice were engineered to express a CD4 transgene under the control of immature CD8 transcriptional elements. In response to CD4-dependent TCR activation, these cells down-regulated the CD4 transgene (as they also did for endogenous CD8), but subsequently re-started CD8 gene transcription to become functional CD8+ T cells. This supports the idea that regardless of TCR and co-receptor specificity, the fate of thymocytes is dictated by the presence or absence of a sustained T cell signal that mediates transcriptional cross-regulation of co-receptor expression. — SJS

Immunity 23, 75 (2005).

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