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.
Brembilla
Nicolò C
NC
Division of Experimental Oncology, Multidisciplinary Oncology Center, Department of Medicine, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.
Weber
Johann
J
Rimoldi
Donata
D
Pradervand
Sylvain
S
Schütz
Frédéric
F
Pantaleo
Giuseppe
G
Rüegg
Curzio
C
Quadroni
Manfredo
M
Harshman
Keith
K
Doucey
Marie-Agnès
MA
D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D015536:Down-Regulation / Q000276:immunology; D015870:Gene Expression / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D040901:Proteomics; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000502:physiology*; D016176:T-Lymphocyte Subsets; D044767:Ubiquitin-Protein Ligases / Q000502:physiology; D015854:Up-Regulation / Q000276:immunology
D016207:Cytokines; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases