Trinity College Dublin researchers, based at St James’s Hospital have provided important insights into the behaviour and metabolic function of a previously largely unknown ‘natural killer’ (NK) immune cell resident in the lungs.

Their findings, published recently in the journal Proceedings of the National Academy of Sciences (PNAS) provide a foundation for further exploration of NK cells for the development of future treatments and therapies for a range of lung diseases, including chronic obstructive pulmonary disease (COPD), cancer and tuberculosis.

The human lung is normally a low glucose environment. During infection, however, glucose becomes readily available and its rapid uptake and metabolism enables immune cells to fight off infections. Natural killer (NK) cells are immune cells tasked with mediating early host defence. The NK cells that live long term in the lung, or in other organs, are called ‘tissue resident’.  Before this study, the metabolic function of human tissue-resident NK cells in the lung was largely unknown.

In this study the researchers found that human tissue-resident NK cells in the lung are metabolically distinct from their counterparts that circulate in the blood. The findings show that lung resident NK cells are poised to rapidly respond to increased glucose in the environment, with an enhanced capacity to increase the metabolism of glucose in order to generate materials that the NK cells need to mount an effective immune response. 

Researchers noted one surprising aspect to their findings, in the readiness of the lung-resident cells to switch on their glycolytic pathways even before an infection occurs, almost as if they are primed and waiting for a ‘sugar rush’ to activate them. This metabolic ‘readiness’ highlights a specialised adaptation of the lung NK cells that makes them particularly effective in their local environment, which could be a key target for future therapies in lung diseases, including cancer and infections.

Lead author of the paper Dr Gráinne Jameson said: “These findings are exciting because they establish that the NK cells in the lung are metabolically different to the NK cells found in blood. This is impactful because it will enable the investigation of dysfunctional NK cells in respiratory diseases and shows that the metabolism of lung resident NKs is a tractable target for inhalable therapies for many setting of lung disease including cancer and infection.”

While this study focused on glucose metabolism, it is important to understand how these NK cells utilise other nutrients, such as fatty acids or amino acids, and how these metabolic pathways might change under different conditions, like chronic infection or cancer.

The researchers now want to explore how the metabolism of lung-resident NK cells may become impaired in different respiratory diseases, such as tuberculosis, COPD, or lung cancer. Understanding what goes wrong in these cells could lead to insights into why some patients have poorer outcomes and what can be done to improve their immune responses.