Inactivation of c-Cbl reverses neonatal lethality and T cell developmental arrest of SLP-76-deficient mice.

Overview

c-Cbl is an adaptor protein that negatively regulates signal transduction events involved in thymic-positive selection. To further characterize the function of c-Cbl in T cell development, we analyzed the effect of c-Cbl inactivation in mice deficient in the scaffolding molecule SLP-76. SLP-76-deficient mice show a high frequency of neonatal lethality; and in surviving mice, T cell development is blocked at the DN3 stage. Inactivation of c-cbl completely reversed the neonatal lethality seen in SLP-76-deficient mice and partially reversed the T cell development arrest in these mice. SLP-76(-/-) Cbl(-/-) mice exhibited marked expansion of polarized T helper type (Th)1 and Th2 cell peripheral CD4(+) T cells, lymphoid infiltrates of parenchymal organs, and premature death. This rescue of T cell development is T cell receptor dependent because it does not occur in recombination activating gene 2(-/-) SLP-76(-/-) Cbl(-/-) triple knockout mice. Analysis of the signal transduction properties of SLP-76(-/-) Cbl(-/-) T cells reveals a novel SLP-76- and linker for activation of T cells-independent pathway of extracellular signal-regulated kinase activation, which is normally down-regulated by c-Cbl.