Epitope‐specific crosslinking of CD45 down‐regulates membrane‐associated tyrosine phosphatase activity and triggers early signalling events in human activated T cells

Summary CD45 engagement by monoclonal antibodies on human activated T cells triggers tumour necrosis factor‐α (TNF‐α) gene transcription in an epitope‐specific manner. To dissect the early signalling events leading to TNF‐α gene expression, we established that CD45 crosslinking resulted in tyrosine...

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Bibliographic Details
Published in:Immunology 2004-12, Vol.113 (4), p.441-452
Main Authors: Spertini, François, Perret‐Menoud, Veronique, Barbier, Nathalie, Chatila, Talal, Barbey, Catherine, Corthesy, Blaise
Format: Article
Language:English
Subjects:
CD45
cell activation
Cells, Cultured
Down-Regulation - immunology
Epitopes, T-Lymphocyte - immunology
Humans
Leukocyte Common Antigens - immunology
Lymphocyte Activation - immunology
Original
Phosphorylation
protein kinase/phosphatase
Protein Tyrosine Phosphatases - metabolism
signal transduction
Signal Transduction - immunology
T cell
T-Lymphocytes - immunology
Tumor Necrosis Factor-alpha - biosynthesis
Tumor Necrosis Factor-alpha - genetics
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Summary:Summary CD45 engagement by monoclonal antibodies on human activated T cells triggers tumour necrosis factor‐α (TNF‐α) gene transcription in an epitope‐specific manner. To dissect the early signalling events leading to TNF‐α gene expression, we established that CD45 crosslinking resulted in tyrosine phosphorylation of p56lck, ZAP‐70, CD3‐ζ, LAT and Vav. This was accompanied by down‐regulation of membrane‐associated protein tyrosine phosphatase activity in the absence of demonstration of enhanced p56lck, p72syk and ZAP‐70 kinase activity, which remained constitutive. These early events eventually triggered an intracellular Ca2+ rise and phosphoinositide turnover. We conclude that down‐regulation of membrane‐associated tyrosine phosphatase activity by CD45 extracytoplasmic domain multimerization led, in an epitope‐specific fashion, to unopposed tyrosine kinase activity and to the activation of the T‐cell receptor/CD3 complex signalling cascade, resulting in TNF‐α gene expression. This model strongly suggests that CD45 extracytoplasmic tail multimerization may contribute to the modulation T‐cell functions.
ISSN:0019-2805
1365-2567
DOI:10.1111/j.1365-2567.2004.01986.x