Impaired T-cell development in the absence of Vav1 and Itk.
Vav1 and the Tec family kinase Itk act in similar T-cell activation pathways. Both molecules interact with members of the Cbl family of E3 ubiquitin ligases, and signaling defects in Vav1(-/-) T cells are rescued upon deletion of Cbl-b. In this study we investigate the relation between Itk and Cbl-b or Vav1 by generating Itk/Cbl-b and Itk/Vav1 double-deficient mice. Deletion of Cbl-b in Itk(-/-) CD4(+) T cells restored proliferation and partially IL-2 production, and also led to a variable rescue of IL-4 production. Thus, Itk and Vav1 act mechanistically similarly in peripheral T cells, since the defects in Itk(-/-) T cells, as in Vav1(-/-) T cells, are rescued if cells are released from the negative regulation mediated by Cbl-b. In addition, only few peripheral CD4(+) and CD8(+) T cells were present in Vav1(-/-)Itk(-/-) mice due to severely impaired thymocyte differentiation. Vav1(-/-)Itk(-/-) thymocyte numbers were strongly reduced compared with WT, Itk(-/-) or Vav1(-/-) mice, and double-positive thymocytes displayed increased cell death and impaired positive selection. Therefore, our data also reveal that the combined activity of Vav1 and Itk is required for proper T-cell development and the generation of the peripheral T-cell pool.
Raberger
Julia
J
Division of Immunobiology, Institute of Immunology, Center for Physiology, Pathophysiology and Immunology, Medical University of Vienna, Vienna, Austria.
Boucheron
Nicole
N
Sakaguchi
Shinya
S
Penninger
Josef M
JM
Ellmeier
Wilfried
W
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D002470:Cell Survival; D007156:Immunologic Memory / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009842:Oligopeptides / Q000276:immunology / Q000378:metabolism; D010641:Phenotype; D011505:Protein-Tyrosine Kinases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D050721:Proto-Oncogene Proteins c-cbl / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism
D009842:Oligopeptides; D051567:Proto-Oncogene Proteins c-vav; C496619:Vav1 protein, mouse; C412863:tynorphin; D050721:Proto-Oncogene Proteins c-cbl; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase