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

• Published in: Nature (London) 2000-07, Vol.406 (6794), p.422-426
• Main Authors: Werlen, Guy, Hausmann, Barbara, Palmer, Ed
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Humanities and Social Sciences; Immunobiology; letter; Lymphoid cells: ontogeny, maturation, markers, receptors, circulation and recirculation; multidisciplinary; Science; Science (multidisciplinary)
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/35019094

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 thymocytes 1 . 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 cascades 2 . 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 selection 3 . 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.