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Sci Signal. 2014 Dec 2;7(354):ra115. doi: 10.1126/scisignal.2005650.

Conformational changes in the T cell receptor differentially determine T cell subset development in mice.

Author information

1
Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, 28049 Madrid, Spain.
2
BIOSS Centre for Biological Signalling Studies, Faculty of Biology, University of Freiburg and Max Planck Institute for Immunobiology and Epigenetics, 79108 Freiburg, Germany.
3
Institut Pasteur, Unité Limphopoïese, INSERM U668, 75015 Paris, France. balarcon@cbm.uam.es ppereira@pasteur.fr.
4
Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, 28049 Madrid, Spain. balarcon@cbm.uam.es ppereira@pasteur.fr.

Abstract

In the thymus, immature T cells differentiate from common precursors to become T cells expressing either the αβ or γδ T cell receptor (TCR) complex. The CD3ε subunit of the TCR complex is thought to transduce ligand-induced conformational changes in the TCR by recruiting the cytosolic adaptor protein Nck. To investigate the role of conformational changes in the TCR in T cell development, we generated mice with a germline mutation (C80G) in the extracellular domain of CD3ε, which prevents the outside-in transmission of conformational changes in the TCR. The development of αβ T cells in the C80G mice was blocked at an early stage that depends on signaling by a precursor form of the TCR. In contrast, the C80G mutation did not impair the development of some subsets of γδ T cells, including Vγ1.1(+) cells; however, development of other γδ T cell subsets was blocked. A similar phenotype was observed in mice with a mutation in the cytoplasmic proline-rich sequence (PRS) of CD3ε, the binding site for Nck. In a genetic complementation test, the PRS CD3ε mutant failed to rescue the wild-type phenotype when expressed in heterozygosity with the C80G mutant. These data suggest that Nck may function as an effector of TCR conformational changes during T cell development. Additional experiments showed differential effects of the C80G mutation on the activation of TCR-dependent signaling pathways, which suggests that there are pathways that are either dependent on or independent of the transmission of conformational change in the receptor.

PMID:
25468995
DOI:
10.1126/scisignal.2005650
[Indexed for MEDLINE]

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