T cell migration is a critical to both the initiation of the immune response as well as the effector phase of T cell function. While many of the cell surface molecules that drive T cell motility have been identified, relatively few intracellular signaling pathways have been investigated that contribute to normal T cell motility. In addition, as leukemic cells from T-acute lumphoblastic leukemia (T-ALL) use conserved pathways to mediate T-ALL migration, it is likely that T-ALL and normal T cells share common signaling components to mediate cell migration. The long term goal of this application is to identify novel signaling pathways that can control normal T cell and T-ALL cell migration. Our proposal seeks to define the mechanism by which these molecules regulate specific aspects of motility. The objective of this particular application is to define the mechanism by which PKC? regulates T cell migration. Based on our preliminary results showing that PKC? can regulate T cell migration, the central hypothesis of this proposal is that PKC? is a novel regulator of T cell and T-ALL migration. Understanding the role of PKC? and novel downstream effectors on T cell and T-ALL migration may provide new therapeutic targets for drug development to treat T-ALL and modulate T cell migration in autoimmune disorders. We will use mouse models to understand how PKC? and other signaling molecules affect T cell migration both in vitro and in vivo. We will also develop a xenograft mouse model of T-ALL migration to study the potential effect of PKC? on T-ALL. Our innovative proposal identifies previously unknown players that regulate the fundamental process of T cell migration. These studies will result in a significant advance in our understanding of the signaling molecules that control T cell and T-ALL cell migration, leading to the identification of novel targets for drug development to treat T-ALL.
The proposed application is relevant to public health because identification of novel molecules that control T cell migration can lead to new targets for therapeutic development which can regulate movement of both normal and leukemic T cells. This study will not only develop fundamental knowledge regarding normal T cell behavior, it will also shed light on what molecules may regulate cancer cell migration.
|Cannon, Judy L; Asperti-Boursin, Francois; Letendre, Kenneth A et al. (2013) PKCýý regulates T cell motility via ezrin-radixin-moesin localization to the uropod. PLoS One 8:e78940|