Oxygen: powering the immune response

A well-functioning immune system is essential for maintaining our health. Every day, we are exposed to germs, like bacteria and viruses, that are in our environment. Additionally, the cells within our body may start to grow abnormally which can make us sick. Our immune system must be ready to respond to, and protect us from, these different challenges. This involves a multi-layered, and complex network of white blood cells and organs that act together to limit infection, destroy the diseased cells within our bodies and defend us from illness.

T cells and their role in the immune system

T cells are a type of white blood cell that are part of the adaptive immune system. They patrol our bodies, moving between different tissues in a relatively inactive state, but are poised to leap into action when they detect signs of infection or disease. T cells can be further described by the roles that they play during an immune response. The research in our lab focuses on CD8 T cells which become short-lived “killer cells” which then seek out and destroy diseased cells before dying-off.

T cells are fine-tuned to respond to infected cells with high specificity. This selectivity helps to prevent the immune system from destroying healthy tissue as diseased cells are being attacked. Additionally, T cells can retain a memory of an infection by a specific microbe. This memory prepares them to react faster, and with an enhanced response, upon re-infection by the same pathogen. Importantly, immune memory provides greater protection against illness caused by the infection; limits the onward spread of the infectious agent to other members of the population; and has the potential to last a lifetime.

Immunologists study T cells in order to understand how they become killer cells; to determine how effectively they protect us from disease in different situations; to know how they move between, and within, different tissues and interact with other cells; and to discover how and when long-lasting memory cells form. As well as providing fundamental understanding into fascinating biological processes, knowledge about T cells provides important opportunities for identifying and refining strategies to improve healthcare. For example, stimulating the formation of immune memory is the basis of successful vaccination. Additionally, harnessing and optimising the function of T cells is the basis for immunotherapies that have the potential to promote remission of cancers, and in some cases even cure them.

T cells: from molecules to function

The ability of T cells to move around the body and fight-off disease is underpinned by their molecular components. The proteins that are required for T cells to respond to infections, and become either killer or memory T cells, are encoded within their DNA. Regulatory networks within the cells direct the production of proteins from these DNA instructions through a process called gene expression. Gene expression in T cells is influenced by a multitude of factors in their surrounding tissue. These factors include messages that signal the presence of diseased cells, as well as nutrients, like sugars and amino acids.

Killer T cells are particularly effective at using nutrients to fuel the production of the proteins that they use to kill diseased cells. T cells take up sugar and convert it to energy in a process called metabolism. Oxygen is essential for powering cellular metabolism, and generating the large amounts of energy needed to make the millions of protein molecules required by each cell. T cells also take up amino acids, which are essential building blocks for proteins. Due to their importance, the quantities of nutrients that are available to killer T cells is known to determine how effectively they can fight diseased cells.

Oxygen and T cell mediated immunity

As T cells move around the body, either when looking for signs of infection, or when they are responding to diseased cells, they are exposed to different levels of oxygen. In some circumstances, they may become starved of oxygen, a phenomenon known as hypoxia. Since oxygen is such a fundamental element for life, cells, including T cells, have evolved many molecular mechanisms to adapt to changes in oxygen levels. These cellular mechanisms can prepare the cells to cope with becoming hypoxic. However, oxygen-dependent signalling pathways also control processes that determine how a T cell will ultimately function, by regulating metabolism, gene expression and how cells respond to other cues in their environment.

Studying how oxygen regulates the function of T cells requires cells to be analysed under precise oxygen conditions, particularly those that mimic the oxygen that T cells will experience when inside an animal. This requires specialised state-of-the-art equipment, and a physiological oxygen and hypoxia lab has been created in the Babraham Institute for this purpose. The instruments in this lab allow researchers in my team to perform detailed molecular studies of the regulatory and biochemical processes within T cells, and how they change in response to higher and lower oxygen levels. We use this molecular understanding to interpret how T cells function in an immune response in an animal.

From this knowledge, our aim is to discover new therapies and improve existing therapies that target T cells to increase their protective capacity against infections and disease.