An adenoviral vector encoding dominant negative Cbl lowers the threshold for T cell activation in post-thymic T cells.
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.
Zha
Yuanyuan
Y
Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
Gajewski
Thomas F
TF
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D018106:CD28 Antigens / Q000276:immunology; D005822:Genetic Vectors / Q000235:genetics; D018664:Interleukin-12 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D013950:Thymus Gland / Q000276:immunology* / Q000378:metabolism*
D018106:CD28 Antigens; D011948:Receptors, Antigen, T-Cell; D018664:Interleukin-12; D050721:Proto-Oncogene Proteins c-cbl