c-Cbl expression levels regulate the functional responses of human central and effector memory CD4 T cells
| Autor: | Curzio Rüegg, Sylvain Pradervand, Frédéric Schütz, Giuseppe Pantaleo, Manfredo Quadroni, Keith Harshman, Marie-Agnès Doucey, Nicolò C. Brembilla, Donata Rimoldi, Johann Weber |
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| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: |
CD4-Positive T-Lymphocytes
Proteomics Ubiquitin-Protein Ligases Immunology Syk Down-Regulation Gene Expression Biology Biochemistry environment and public health FYN T-Lymphocyte Subsets hemic and lymphatic diseases medicine Cytotoxic T cell Humans IL-2 receptor Proto-Oncogene Proteins c-cbl Cells Cultured Immunobiology Cell Proliferation T-cell receptor Cell Biology Hematology Molecular biology Cell biology Up-Regulation enzymes and coenzymes (carbohydrates) medicine.anatomical_structure Cytokines Signal transduction biological phenomena cell phenomena and immunity Memory T cell Immunologic Memory CD8 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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