Cbl Inhibits Vav-1-Independent T Cell Differentiation (36.56)

Abstract

Abstract Cbl, an E3 ubiquitin ligase, negatively regulates signal transduction events involved in thymic development. Most recently, we reported that inactivation of Cbl rescues the defect of T cell development in mice expressing a mutant SLP-76 that lacks the ability to bind Vav. The defect in T cell development in these SLP-76 mutant mice is similar to that of Vav1 deficient mice, marked by a block at the DN3 stage. It was therefore possible that Cbl inactivation facilitates T cell development through a Vav signaling pathway independent of SLP-76. To assess this possibility, we generated Cbl-/-Vav1-/- double knockout mouse and hypothesized that Cbl inactivation would not be able to reverse the defects of T cell development in Vav1-/- mice. Unexpectedly, the inactivation of Cbl rescued T cell development of Vav1-/- mice. Rescued development in Cbl-/-Vav1-/- DP thymocytes is associated with enhanced tyrosine-phosphorylation of signaling molecules, including Vav2, PLC-gama1 and ERKs in response to TCR stimulation. Therefore, Cbl normally inhibits a T cell differentiation pathway which is independent of Vav-1. The role of Vav2 and other components of this pathway remain to be elucidated.