Submitted January 17, 2008
Accepted April 17, 2008
c-Cbl expression regulates the functional response of human central versus effector memory CD4 T cells
Nicolo C Brembilla, Johann Weber, Donata Rimoldi, Sylvain Pradervand, Frederic Schutz, Giuseppe Pantaleo, Curzio Ruegg, Manfredo Quadroni, Keith Harshman, and Marie-Agnes Doucey*
Division of Experimental Oncology, CHUV, University of Lausanne, Lausanne, Switzerland
DNA Array Facility, Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
Ludwig Institute for Cancer Research, Lausanne, Switzerland
Bioinformatics Core Facility, Swiss Institute of Bioinformatics, Lausanne, Switzerland
Laboratory of AIDS Immunopathogenesis, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
Protein Analysis Facility, University of Lausanne, Lausanne, Switzerland
* Corresponding author; email: marie-agnes.doucey{at}unil.ch.
The biochemical mechanisms controlling the diverse functional outcomes of human central (CM) and effector (EM) memory T cell responses triggered through the 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 to 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 the 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. Indeed, increasing c-Cbl content of EM cells to the same level of CM cells using cytosolic transduction, we impaired their proliferation and cytokine production. This regulatory mechanism is primarily dependent on c-Cbl E3 ubiquitin ligase activity as evidenced by the weaker impact of enzymatically deficient c-Cbl C381A mutant on EM cells functions. Our study identifies c-Cbl as a critical regulator of the functional responses of memory T cell subsets and provides, for the first time in humans, a mechanism controlling the functional heterogeneity of memory CD4 cells.
