MRC National Institute for Medical Research, London
Science for Health
Timing is everything when making T cells
24 March 2010
T lymphocytes of the adaptive immune system come in two principal types: CD4 helper and CD8 killer T cells. Both are generated within the thymus from common thymocyte precursors during the process of positive selection, in which only T cells with 'useful' antigen receptors are allowed to survive and mature. The decision by common thymocyte precursors to become either CD4 or CD8 T cells is a complex process requiring thymocytes to respond to subtle and varying environmental signals. The T cell antigen receptor (TCR) itself plays a central role in transmitting these signals.
Benedict Seddon (pictured) and his group in NIMR's Division of Immune Cell Biology has investigated the role of the tyrosine kinase Zap70, a protein essential for TCR signaling and thymocyte development in the CD4/CD8 lineage decision. They developed an inducible Zap70 transgenic model that allowed them to control expression of Zap70 and therefore thymocyte development. This revealed that the different lineages underwent development with very distinct kinetics, such that CD4 T cells develop rapidly, within hours, while CD8 T cells took several days to differentiate. Surprisingly, they found that in normal mice Zap70 is dynamically upregulated during development, creating a temporal gradient of TCR signaling activity. They showed that this gradient is essential for normal thymocyte development since it allows the two lineages to develop at different times and at different thresholds of TCR signaling.
T cell development
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Kinetics of T cell development following resumption of Zap70 dependent signaling
How developing thymocytes decide whether they will become CD4 helper or CD8 killer T cells is a question that has challenged immunologists for decades. Uncovering this temporal gradient in a key lymphocyte signaling protein, Zap70, reveals for the first time just how important the timing of signaling is to this key developmental decision. This is a dimension of T cell development that had hitherto been largely overlooked.
Benedict Seddon
Original article
The research findings are published in full in:
Saini, M., Sinclair, C., Tolaini, M., Sakaguchi, S. and Seddon B. (2010).
Regulation of Zap70 expression during thymic development allows temporal separation of CD4 and CD8 repertoire selection at different signalling thresholds.
Science Signaling, 3(114): ra23. Publisher fulltext
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