Altered thymic positive selection and intracellular signals in Cb1-deficient mice

Cbl is the product of the protooncogene c-cbl and is involved in T cell ant igen receptor (TCR)-mediated signaling. To understand the role of Cbl for i mmune system development and function, we generated a Cbl-deficient mouse s train. In Cbl-deficient mice, positive selection of the thymocytes expressi ng major histocompatibility complex class II-restricted transgenic TCR was significantly enhanced. Two factors may have contributed to the altered thy mic selection. First, Cbl deficiency markedly up-regulated the activity of ZAP-70 and mitogen-activated protein kinases. The mitogen-activated protein kinase pathway was shown previously to be involved in thymic positive sele ction. Second, Cbl-deficient thymocytes expressed CD3 and CD4 molecules at higher levels, which consequently may increase the avidity of TCR/major his tocompatibility complex/coreceptor interaction, Thus, Cbl plays a novel rol e in modulating TCR-mediated multiple signaling pathways and fine-tunes the signaling threshold for thymic selection.