c-Cbl expression levels regulate the functional responses of human central and effector memory CD4 T cells.

Details

Serval ID
serval:BIB_6DDFA2713E61
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
c-Cbl expression levels regulate the functional responses of human central and effector memory CD4 T cells.
Journal
Blood
Author(s)
Brembilla N.C., Weber J., Rimoldi D., Pradervand S., Schütz F., Pantaleo G., Rüegg C., Quadroni M., Harshman K., Doucey M.A.
ISSN
1528-0020[electronic]
Publication state
Published
Issued date
2008
Volume
112
Number
3
Pages
652-660
Language
english
Abstract
The biochemical mechanisms controlling the diverse functional outcomes of human central memory (CM) and effector memory (EM) T-cell responses triggered through the T-cell receptor (TCR) remain poorly understood. We implemented reverse phase protein arrays to profile TCR signaling components in human CD8 and CD4 memory T-cell subsets isolated ex vivo. As compared with CD4 CM cells, EM cells express statistically significant increased amounts of SLP-76 and reduced levels of c-Cbl, Syk, Fyn, and LAT. Moreover, in EM cells reduced expression of negative regulator c-Cbl correlates with expression of c-Cbl kinases (Syk and Fyn), PI3K, and LAT. Importantly, consistent with reduced expression of c-Cbl, EM cells display a lower functional threshold than CM cells. Increasing c-Cbl content of EM cells to the same level as that of CM cells using cytosolic transduction, we impaired their proliferation and cytokine production. This regulatory mechanism depends primarily on c-Cbl E3 ubiquitin ligase activity as evidenced by the weaker impact of enzymatically deficient c-Cbl C381A mutant on EM cell functions. Our study reports c-Cbl as a critical regulator of the functional responses of memory T cell subsets and identifies for the first time in humans a mechanism controlling the functional heterogeneity of memory CD4 cells.
Keywords
CD4-Positive T-Lymphocytes, Cell Proliferation, Cells, Cultured, Cytokines, Down-Regulation, Gene Expression, Humans, Immunologic Memory, Proteomics, Proto-Oncogene Proteins c-cbl, T-Lymphocyte Subsets, Ubiquitin-Protein Ligases, Up-Regulation
Pubmed
Web of science
Open Access
Yes
Create date
01/04/2009 15:33
Last modification date
20/08/2019 15:27
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