A motif in the αβ T-cell receptor controls positive selection by modulating ERK activity

Guy Werlen, Barbara Hausmann and Ed Palmer ()
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Guy Werlen: Basel Institute for Immunology
Barbara Hausmann: Basel Institute for Immunology
Ed Palmer: Basel Institute for Immunology

Nature, 2000, vol. 406, issue 6794, 422-426

Abstract: 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.

Date: 2000
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DOI: 10.1038/35019094

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