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T-cell receptor (TCR) triggering results in a cascade of intracellular tyrosine phosphorylation events that ultimately leads to T-cell activation. It is dependent on changes in the relative activities of membrane-associated tyrosine kinases and phosphatases near the engaged TCR. CD45 and CD148 are transmembrane tyrosine phosphatases with large ectodomains that have activatory and inhibitory effects on TCR triggering. This study investigates whether and how the ectodomains of CD45 and CD148 modulate their inhibitory effect on TCR signaling. Expression in T cells of forms of these phosphatases with truncated ectodomains inhibited TCR triggering. In contrast, when these phosphatases were expressed with large ectodomains, they had no inhibitory effect. Imaging studies revealed that truncation of the ectodomains enhanced colocalization of these phosphatases with ligated TCR at the immunological synapse. Our results suggest that the large ectodomains of CD45 and CD148 modulate their inhibitory effect by enabling their passive, size-based segregation from ligated TCR, supporting the kinetic-segregation model of TCR triggering.

Original publication

DOI

10.1182/blood-2012-07-442251

Type

Journal article

Journal

Blood

Publication Date

05/2013

Volume

121

Pages

4295 - 4302

Addresses

Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.

Keywords

CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cell Line, Animals, Mice, Antigens, CD45, Receptors, Antigen, T-Cell, Interleukin-2, Lymphocyte Activation, Signal Transduction, Mutagenesis, Protein Structure, Tertiary, Protein Binding, Structure-Activity Relationship, Models, Chemical, Receptor-Like Protein Tyrosine Phosphatases, Class 3