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Blood, 1 August 2008, Vol. 112, No. 3, pp. 652-660. Prepublished online as a Blood First Edition Paper on May 27, 2008; DOI 10.1182/blood-2008-01-134486. This Article Full Text Full Text (PDF) Supplemental Table and Figures All Versions of this Article: blood-2008-01-134486v1 112/3/652    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Brembilla, N. C. Articles by Doucey, M.-A. Search for Related Content PubMed PubMed Citation Articles by Brembilla, N. C. Articles by Doucey, M.-A. Related Collections Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY c-Cbl expression levels regulate the functional responses of human central and effector memory CD4 T cells Nicolò C. Brembilla1,2, Johann Weber3, Donata Rimoldi4, Sylvain Pradervand3,5, Frédéric Schütz5, Giuseppe Pantaleo2, Curzio Rüegg1, Manfredo Quadroni6, Keith Harshman3, and Marie-Agnès Doucey1,6 1 Division of Experimental Oncology, Multidisciplinary Oncology Center and 2 Laboratory of AIDS Immunopathogenesis, Division of Immunology and Allergy, Department of Medicine, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne; 3 DNA Array Facility, Center for Integrative Genomics, University of Lausanne, Lausanne; 4 Ludwig Institute for Cancer Research, Lausanne Branch, Epalinges; 5 Bioinformatics Core Facility, Swiss Institute of Bioinformatics, Lausanne; and 6 Protein Analysis Facility, Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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