Grant: Operating Grant

T cells are critical mediators of the immune response, but they are also prime targets for cancerous transformation. Therefore, elucidating how T cells are made from stem cells is of paramount importance for understanding both normal immune function and leukemia. We have discovered that two different proteins, HEBAlt and HEBCan, are important regulators of the developmental pathways that allow stem cells to adopt a T-cell identity. Our studies suggest that both HEBAlt and HEBCan are needed to make T cells, whereas an imbalance of these factors can lead to a divergence into other immune cell fates. Specifically, cells with high levels of HEBAlt may become natural killer (NK) cells, whereas high levels of HEBCan may re-direct cells to become dendritic cells (DCs). Moreover, we have found that HEBAlt promotes cell growth whereas HEBCan inhibits it, suggesting that deregulation of HEBAlt could predispose developing T cells to leukemic transformation. To better understand how HEBAlt and HEBCan work together to direct cells to become T cells, we are using transgenic mice that express either HEBAlt or HEBCan to identify the genes under their control. These genes encode other proteins that work in conjunction with HEBAlt and/or HEBCan in molecular networks to give the cells their specific functions, and defining these networks will enable us to perturb them towards a desired outcome. We also aim to understand how the unique portion of HEBAlt, the Alt domain, allows HEBAlt to function differently than HEBCan. We will change portions of the Alt domain and then see whether the ability of HEBAlt to control gene expression is affected. These studies will provide important insights into the molecular control of immune cell development, and are likely to provide new targets for diagnostic and therapeutic applications for immunodeficiencies, autoimmune diseases, and leukemia.