Researchers at St. Jude Children’s Research Hospital now have evidence that special T cells, responsible for maintaining a balanced immune response, are vulnerable to depletion, which interferes with their normal functioning and can contribute to allergic reactions.
Regulatory T cells are a small population of lymphocytes that control the immune system and help prevent asthma, allergies, and autoimmune disorders such as multiple sclerosis and lupus.
The researchers focused on liver kinase B1 (LKB1), a protein that controls cell growth and metabolism. Working in mice, the researchers showed how, at a molecular level, the loss of LKB1 in regulatory T cells disrupts cellular metabolism and their function. The mice developed a fatal inflammatory disease and their regulatory T cells showed functional, molecular, and other changes consistent with functional exhaustion. It is known that regulatory T cells can “rest” or, conversely, be activated. Observations show that they can also become functionally depleted.
The results indicate functional depletion of regulatory T cells as a possible culprit in the immune response associated with an allergic reaction known as the Th2 response. The work suggests a possible new therapeutic approach for autoimmune disorders that will be developed to enhance the function of regulatory T cells by modulating cellular metabolism, the authors reported.
The study also highlighted the role of metabolism in immune function. Removal of LKB1 in regulatory T cells disrupted metabolic pathways that support mitochondrial health and function. Mitochondria generate energy to power cells. LKB1 links immunological signals and cellular metabolic programs, especially those associated with mitochondrial function.
The researchers noted the ability of regulatory T cells to partially neutralize the Th2 response to LKB1’s ability to inhibit the expression of the cell surface PD-1 receptor and possibly other receptors. In normal T cells, PD-1 helps to inhibit their activity and immune response to prevent unwanted immune responses that lead to autoimmune diseases.
The loss of LKB1 led to an increase in the production of PD-1 by regulatory T cells. This increase inhibited the ability of regulatory T cells to suppress the Th2 immune response in mice. Blocking PD-1 activity significantly restored the ability of regulatory T cells to suppress the Th2 immune response.
In addition, the researchers found evidence that LKB1 helped control the Th2 response through additional processes. For example, LKB1 also helped to suppress cell surface markers on immune cells called dendritic cells that activated the allergic response. Loss of LKB1 by regulatory T cells has also been associated with increased levels of signaling molecules or cytokines associated with the Th2 immune response.
The researchers examined other details about the selective role of LKB1 in regulatory T cells, including the fact that the molecule unexpectedly works through the Wnt signaling pathway to interfere with the regulatory function of T cells. LKB1 is known to operate in a variety of ways, mainly through the mTORC1 and AMPK signaling channels.