Interrogating NRK1 activity as a central regulator of CD4+ T cell metabolism, fate and function

T cells are a critical part of our immune system which co-ordinate the activity of all other immune cells (white blood cells) to protect us from infections and cancer. However, sometimes T cells can be over-active, which can be harmful. When this occurs it can cause diseases such as rheumatoid arthritis, multiple sclerosis and diabetes. These are known as inflammatory or autoimmune diseases, a process where the body's own immune cells attack it. Current therapies for these diseases do not always work well, meaning that many patients still suffer with severe symptoms and these diseases still place a significant burden on the NHS.

In the last decade our understanding of how T cells work has been transformed. We have learned that the activity of T cells is very tightly linked to a series of chemical processes known as metabolism, which occurs in every cell of the human body. These processes are used to break down nutrients such as sugar to provide energy and building blocks for the cell. Recent research has revealed that T cells can dramatically change how they break down nutrients when they carry out their protective (normal activity) or harmful (over-active) functions. Studies in patients with infectious and autoimmunity have revealed that these processes are often abnormal in T cells in these conditions. It may be possible therefore, that with new drugs that correct these changes in metabolism, we can restore normal, safe T cell activity, and better treat these diseases.

This proposal will investigate one possible pathway to control T cell metabolism and restore their normal function. Specifically, I propose to test how the production of a molecule called nicotinamide adenine dinucleotide (NAD) is linked to T cell metabolism and their protective and harmful activity. NAD is produced from vitamin B3 and is required for all stages of the breakdown of sugar and other nutrients in cells. It has already identified that when T cells are activated (switched on) in the laboratory, they turn on an enzyme called NRK1 which plays an important role in making NAD from vitamin B3. Additionally, when NRK1 is not active, T cells have much lower rates of metabolism and produce much less of certain key immune signals. I now propose to build on these observations to understand in much more depth precisely how NRK1 controls T cell activity. As part of this project I will also change NRK1 activity in T cells in laboratory models of infection and autoimmunity. This will help us to test whether new drugs targeting this molecule might be helpful in these conditions.

CD4+ T cells co-ordinate the immune response and are essential for adaptive immunity and protection from infectious disease. Consistently, CD4+ T cell dysfunction is associated with uncontrolled infection, whilst, conversely, their dysregulated activity is implicated in chronic inflammatory and immune-mediated disease. Despite recent therapeutic advances, these conditions continue to cause significant morbidity to many patients and place substantial financial burdens on the NHS. In the last decade, research has revealed that CD4+ T cell fate and function are fundamentally underpinned by dynamic changes in their metabolism. Furthermore, T cell metabolic dysfunction is reported in chronic viral infection and numerous autoinflammatory diseases, including systemic lupus erythematosus (SLE), type I diabetes and multiple sclerosis (MS). This has raised the exciting possibility of targeting CD4+ T cell metabolism as a novel therapeutic approach to correct their activity in these conditions, which has support from initial laboratory studies. Yet, the concerted activity of numerous diverse and flexible metabolic pathways supports T cell function, meaning that targeting one enzyme or pathway in isolation may have limited efficacy. Therefore, identification of central metabolic regulators in these cells would significantly advance this area of research and translation into new therapies. Our pilot data identify that activity of the NAD synthesis enzyme, nicotinamide riboside kinase 1 (NRK1) within CD4+ T cells has a profound effect on their overall metabolic capacity and immune function, and may therefore be one such central regulator. The proposed research will interrogate this in significant depth, employing cutting-edge metabolic analyses alongside established immunological approaches including experimental models of infectious and immune-mediated disease.