T cell-to-T cell clustering enhances NF-kappaB activity by a PI3K signal mediated by Cbl-b and Rho

Full activation of T cells requires the binding of antigen to the T cell receptor and stimulation of the CD28 molecule, a process which typically occurs when T cells bind to an antigen presenting cell. The transcription factor, NF-kappaB, is an integration point for these two signals and its activat...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2005-07, Vol.332 (4), p.1133-1139
Main Authors: Herndon, Thomas M, Pirone, Dana M, Tsokos, George C, Chen, Christopher S
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - metabolism
CD28 Antigens - biosynthesis
Cell Communication
Cluster Analysis
Genes, Dominant
Genes, Reporter
Humans
Inflammation
Jurkat Cells
Luciferases - metabolism
Models, Biological
NF-kappa B - metabolism
Oncogene Protein v-cbl
Phosphatidylinositol 3-Kinases - metabolism
Proto-Oncogene Proteins c-cbl
Retroviridae Proteins, Oncogenic - metabolism
rho GTP-Binding Proteins - metabolism
Signal Transduction
T-Lymphocytes - metabolism
Transfection
Ubiquitin-Protein Ligases - metabolism
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Summary:Full activation of T cells requires the binding of antigen to the T cell receptor and stimulation of the CD28 molecule, a process which typically occurs when T cells bind to an antigen presenting cell. The transcription factor, NF-kappaB, is an integration point for these two signals and its activation is critical for T cell function. Using antibodies to the TCR and CD28 molecules to activate Jurkat T cells, we show that cells that were permitted to aggregate into multi-cellular clusters increased NF-kappaB activity compared to unclustered cells. Inhibition of PI3K signaling with wortmannin decreased the clustering-mediated NF-kappaB signal. Over-expression of a dominant negative form of Cbl-b, an endogenous inhibitor of PI3K, in unclustered cells rescued NF-kappaB activation to the same levels caused by cell clustering. Inhibiting signaling through Rho with dominant negative RhoA abrogated both clustering-mediated and dominant negative Cbl-b-mediated NF-kappaB inactivation, but not TCR/CD28 mediated NF-kappaB activation. Taken together, these results suggest that in addition to pathways stimulated by classical T cell-APC interactions, another signal arising from T cell clustering can enhance activation.
ISSN:0006-291X