Impaired T-cell development in the absence of Vav1 and Itk.
Eur J Immunol
; 38(12): 3530-42, 2008 Dec.
Article
en En
| MEDLINE
| ID: mdl-19009524
ABSTRACT
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.
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MEDLINE
Asunto principal:
Proteínas Tirosina Quinasas
/
Linfocitos T
/
Diferenciación Celular
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Proteínas Proto-Oncogénicas c-vav
Límite:
Animals
Idioma:
En
Año:
2008
Tipo del documento:
Article