NKG2D IN T-CELLS

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

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 Obiettivo del progetto (Objective)

'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.'

Introduzione (Teaser)

Despite medical advances, immunity is a process that is incompletely understood. Detailed investigation into the biology of the immune system is expected to aid in the fight against pathogens.

Descrizione progetto (Article)

Vaccination essentially educates the immune system against pathogens before they are encountered, thereby protecting against infectious diseases. However, infectious diseases such as HIV and Hepatitis C remain a serious health issue.

Research efforts to address this problem have recognised the natural killer group 2-member D (NKG2D) receptor as an important mediator of the cytotoxic potential of CD8 T cells. Cellular immunity mediated by memory CD8 T-cells provides protection against infections and the development of cancer. NKG2D is expressed on effector and memory T-cells and binds ligands which are up-regulated in infected and cancer cells.

Scientists on the EU-funded 'Memory control; the role of NKG2D and the T-cell receptor in memory T cell biology' (NKG2D IN T-CELLS) project wished to explore this further by elucidating the role of NKG2D in the formation, maintenance and function of memory CD8 T cells. For this purpose, they generated mice deficient in the NKG2D receptor and studied their T cells.

They found that when these mice were infected with virus, they could mount normal immune responses but proved less efficient at forming memory cells. Hence, NKG2D deficiency resulted in reduced protection against secondary infection. Further investigation into the function of NKG2D-deficient T cells indicated that the formation of immunological memory and not the actual function of these cells were affected.

Work into the mechanism of NKG2D function unveiled potential molecules (DAP10) and cytokines (IL-15) that promote memory cell formation. Researchers found that NKG2D was essential for the survival of memory cell precursors via PI3K pathway signalling.

Taken together, project outcomes clearly underscore the importance of NKG2D in immunological memory formation and antiviral immunity. They also support the rationale of targeting NKG2D as a means of enhancing T cell cytotoxicity against viral targets or tumour cells.