Abstract
Positive selection allows thymocytes that recognize an individual's own major histocompatibility complex (self-MHC) molecules to survive and differentiate, whereas negative selection removes overtly self-reactive thymocytes1. Although both forms of thymic selection are mediated by the αβ T-cell receptor (TCR) and require self-MHC recognition, an important question is whether they are controlled by distinct signalling cascades2. We have shown that mutation of an essential motif within the TCR α-chain-connecting peptide domain (α-CPM) profoundly affects positive but not negative selection3. Using transgenic mice expressing a mutant α-CPM TCR we examined the contribution of several mitogen-activated protein kinase (MAPK) cascades to thymic selection. Here we show that in thymocytes expressing a mutant α-CPM receptor, a positively selecting peptide failed to activate the extracellular signal-regulated kinase (ERK), although other MAPK cascades were induced normally. The defect in ERK activation was associated with impaired recruitment of the activated tyrosine kinases Lck and ZAP-70, phosphorylated forms of the TCR component CD3ζ and the adaptor protein LAT to detergent-insoluble glycolipid-enriched microdomains (DIGs). Therefore, an intact DIG-associated signalosome is essential for sustained ERK activation, which leads to positive selection.
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Acknowledgements
We thank F. Carbone, M. J. Bevan and D. Kioussis for transgenic mice expressing wild-type OT-1 receptors; A. Peter for generating mutant α-CPM TCR constructs; U. Müller for generation of mutant transgenic mice; T. Potter for T2-Kb cells; M. Daniels, K. Hogquist and S. Jameson for tetramers; L. Samelson for LAT antisera; S. Stotz and T. Harder for discussions; and E. Jacinto, T. Baldari, P. Kisielow and J. Kirberg for reading the manuscript. The Basel Institute for Immunology was founded and is supported by F. Hoffmann-LaRoche Ltd.
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Werlen, G., Hausmann, B. & Palmer, E. A motif in the αβ T-cell receptor controls positive selection by modulating ERK activity. Nature 406, 422–426 (2000). https://doi.org/10.1038/35019094
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DOI: https://doi.org/10.1038/35019094
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