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

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.

Sujets

CD4-Positive T-Lympho...

Cell Proliferation

Cells, Cultured

Cytokines

Down-Regulation

Gene Expression

Humans

Immunologic Memory

Proteomics

Proto-Oncogene Protei...

T-Lymphocyte Subsets

Ubiquitin-Protein Lig...

Up-Regulation

PID Serval

serval:BIB_6DDFA2713E61

DOI

10.1182/blood-2008-01-134486

PMID

18505781

WOS

000258257900032

Permalien

https://iris.unil.ch/handle/iris/224708

Open Access

Oui

Date de création

2009-04-01T13:33:27.136Z

Date de création dans IRIS

2025-05-21T04:35:52Z