An adenoviral vector encoding dominant negative Cbl lowers the threshold for T cell activation in post-thymic T cells |
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Authors: | Zha Yuanyuan Gajewski Thomas F |
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Institution: | a Department of Pathology, University of Chicago, Chicago, IL 60637, USA b Department of Medicine, University of Chicago, Chicago, IL 60637, USA |
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Abstract: | Cbl family ubiquitin ligases act as key negative regulators of TCR signaling. Knockout mice lacking Cbl-b and c-Cbl show augmented T cell activation and CD28-independent IL-2 production. In order to study Cbl function directly in post-thymic T cells, a DN Cbl adenovirus was generated for transduction of T cells from Coxsackie/adenovirus receptor (CAR) transgenic (Tg) mice. We show that dominant negative (DN) Cbl-transduced CD4+ T cells exhibited enhanced IL-2 production upon TCR/CD28 engagement compared with empty adenoviral vector-transduced cells. This augmentation was reflected at both IL-2 mRNA and protein level, and correlated with increased protein phosphorylation of Vav, Akt, ERK, and p38MAPK. Our results indicate that introduction of dominant negative Cbl can potentiate activation of post-thymic CD4+ T cells, which argues for development of strategies to interfere with Cbl function as a method of immunopotentiation. |
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Keywords: | CD4+ T cells Cbl CD28 costimulation T cell activation |
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