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

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  • Guy Werlen

    (Basel Institute for Immunology)

  • Barbara Hausmann

    (Basel Institute for Immunology)

  • Ed Palmer

    (Basel Institute for Immunology)

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.

Suggested Citation

  • Guy Werlen & Barbara Hausmann & Ed Palmer, 2000. "A motif in the αβ T-cell receptor controls positive selection by modulating ERK activity," Nature, Nature, vol. 406(6794), pages 422-426, July.
  • Handle: RePEc:nat:nature:v:406:y:2000:i:6794:d:10.1038_35019094
    DOI: 10.1038/35019094
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    Cited by:

    1. Guy Werlen & Mei-Ling Li & Luca Tottone & Victoria da Silva-Diz & Xiaoyang Su & Daniel Herranz & Estela Jacinto, 2022. "Dietary glucosamine overcomes the defects in αβ-T cell ontogeny caused by the loss of de novo hexosamine biosynthesis," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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