Our immune system has to be able to identify and attack invaders or cancerous cells while also recognizing and ignoring our own cells. A type of immune cell called regulatory T cells act to control the immune response. While they are important for preventing the immune system from attacking cells of the body, they can, unfortunately, limit the immune response to tumors. New work has investigated how the reactivity of T cells is kept in check, both to prevent autoimmunity but which also stops any anti-cancer effect. The study, published in Cell Metabolism, also showed it may be possible to use a highly tailored diet to address the metabolic state that arises in regulatory T cells, and change it to eliminate autoimmune disease.
"Our immune system is needed for a healthy body function and protects us from all kinds of infections. Particularly important in this respect are T cells, and specifically regulatory T cells. Although these represent only a small fraction of all T cells, they are crucial to keep our immune system in check" explained Professor Dirk Brenner, FNR ATTRACT fellow and Head of Experimental & Molecular Immunology at the Luxembourg Institute of Health (LIH). "If regulatory T cells are not functional, the immune system gets out of control and turns against its own body. This can lead to detrimental autoimmune diseases like multiple sclerosis, type I diabetes, or arthritis. However, a highly reactive immune system can kill cancer cells very efficiently. This has led to the development of 'checkpoint inhibitors,' specific drugs that unleash an immune system attack on cancer cells and which won the Nobel Prize in Medicine in 2018".
Normal cellular functions like division can produce molecules called free radicals, and exposure to toxins or neighboring cancer cells can also increase the production of free radicals. When free radicals levels get so high that the cell can't dispose of them, it triggers oxidative stress, which damages the cells. In this work, the researchers investigated how regulatory T cells deal with free radicals and oxidative stress.
"Free oxygen radicals are neutralized by antioxidants and the major antioxidant in T cells is a molecule known as glutathione. We were surprised when we realized that regulatory T cells had about three times as much glutathione as other T cells. This pointed to an important function," said the first author of the study, Henry Kurniawan, a graduate candidate in the Brenner lab.
If metabolism can be modified in regulatory T cells, it can alter the intensity of the immune reaction. Using a mouse model, the researchers deleted a gene that is critical for glutathione production from a small group of regulatory T cells. When the gene was removed, free radicals began to accumulate in the altered T cells, and they stopped acting to control the immune system. A fatal autoimmune disease then set in.
The researchers also found that the metabolism of an amino acid called serine was dramatically increased in the glutathione-depleted T cells. The team used the findings to create a diet aimed at addressing these metabolic changes. The diet they engineered lacked serine, as well as glycine, a close relative. The severe autoimmunity that had been observed in the mouse model was halted.
"Importantly, our study shows that the absence of only 2 out of 22 amino acids can cure a complex autoimmune disease. Therefore, elucidating the exact metabolic and molecular basis of a disease offers the possibility to correct these metabolic abnormalities through a special diet that is precisely adapted to the delineated disease mechanism. Our study might be a first step in the direction of the personalized treatment of metabolic diseases and autoimmunity," said Brenner.
"The relationship between glutathione, free radicals, and serine can be used as a switch to modulate immune cell activation. A higher immune cell activity is beneficial for cancer patients. We were intrigued by the idea of using our findings also to boost anti-tumor responses" he added.
When the glutathione levels in regulatory T cells went down, immune activation increased, and the mouse model began to reject tumors.
"These astonishing results show the enormous potential of tweaking metabolism to prevent autoimmunity and target cancer. This could pave the way for the development of a new generation of immunotherapies," noted Prof Markus Ollert, Director of LIH's Department of Infection and Immunity.
Sources: AAAS/Eurekalert! via Luxembourg Institute of Health, Cell Metabolism
