CD3δ couples T-cell receptor signalling to ERK activation and thymocyte positive selection

Pilar Delgado, Edgar Fernández (), Vibhuti Dave, Dietmar Kappes and Balbino Alarcón ()
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Pilar Delgado: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid
Edgar Fernández: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid
Vibhuti Dave: Fox Chase Cancer Center
Dietmar Kappes: Fox Chase Cancer Center
Balbino Alarcón: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid

Nature, 2000, vol. 406, issue 6794, 426-430

Abstract: Abstract Thymocytes from mice lacking the CD3δ chain of the T-cell receptor (TCR), unlike those of other CD3-deficient mice1,2, progress from a CD4-CD8- double-negative to a CD4+CD8+ double-positive stage. However, CD3δ-/- double-positive cells fail to undergo positive selection, by which double-positive cells differentiate into more mature thymocytes3. Positive selection is also impaired in mice expressing inactive components of the Ras/mitogen activated protein (MAP) kinase signalling pathway4,5,6. Here we show that CD3δ-/- thymocytes are defective in the induction of extracellular signal-regulated protein kinase (ERK) MAP kinases upon TCR engagement, whereas activation of other MAP kinases is unaffected. The requirement for CD3δ maps to its extracellular or transmembrane domains, or both, as expression of a tail-less CD3δ rescues both ERK activation and positive selection in CD3δ-/- mice. Furthermore, the defect correlates with severely impaired tyrosine phosphorylation of the linker protein LAT, and of the CD3ζ chain that is localized to membrane lipid rafts upon TCR engagement. Our data indicate that the blockade of positive selection of CD3δ-/- thymocytes may derive from defective tyrosine phosphorylation of CD3ζ in lipid rafts, resulting in impaired activation of the LAT/Ras/ERK pathway.

Date: 2000
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DOI: 10.1038/35019102

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