NKG2D in T-cells · Memory Control; The role of NKG2D and the T-cell receptor in memory T cell biology

Despite our advances in medical sciences, infectious diseases such as HIV and Hepatitis C remain an important health problem for our society. Also, targeting the immune system towards cancer is a promising therapy to fight this disease. Cellular immunity mediated by memory CD8 T-cells provides vital protection against infections and the development of tumors. Understanding the formation and maintenance of these cells is therefore an essential step towards using these cells in a therapeutic way.Maintenance of T-cells must balance the need of their protective responses with the cost of sustaining specialized cells which may never again in life be required. The mechanisms controlling this balance are largely unknown. NKG2D is expressed on effector and memory T-cells and binds ligands which are upregulated in infected and oncogenic cells. NKG2D signaling promotes survival of lymphocytes via activation of the PI3K-signaling pathway. NK cells deficient for NKG2D undergo apoptosis more rapidly, showing its function in mediating viability and suggesting a role in memory T-cell maintenance. The T-cell receptor (TCR) has also been shown to be important for T-cell survival. TCR deficiency leads to a higher turn-over of memory T-cells. The pro-survival signaling cascade engaged by the TCR is unknown, but recent insights in tonic B-cell receptor signaling suggest involvement of the PI3K pathway.This research project will investigate the role of NKG2D, the TCR and their intracellular signaling in memory T-cell biology. We will conduct our studies on a molecular, cellular and physiological level, using unique mouse models and advanced immunological techniques. We consider our project scientifically and socially relevant, as it will provide new insights in the mechanisms controlling memory T-cell biology. Understanding these processes will provide new leads for future research and their manipulation may pose promising future targets for the development of more efficient vaccines.