Many people don’t know it, but in their chest, between the upper tips of their lungs, there is a small gland that resembles a thyme flower: the thymus, which weighs barely a gram. White blood cells – the human body’s defenses – are made in the bones, but some migrate to the thymus gland, where they mature into cytotoxic T lymphocytes, the real killers in the immune system that can even destroy cancer cells. Now a team led by Spanish biochemist Miguel Reina has found a way to strengthen these soldiers and improve their immunity against tumors and infections. Their discovery was published this Wednesday in the journal Nature.
T lymphocytes leave the thymus (hence the T) and circulate through the blood. For example, when a virus attacks the intestines, these white blood cells travel there and kill the infected cells. Once the problem is solved, the T lymphocytes remain in the organ as permanent sentinels for decades. This is called tissue-resident memory. Reina uses his own life as an example to explain the phenomenon. The Barcelona-born biochemist conducts research at the University of California in San Diego in the USA and briefly visited a German center a decade ago. “Lymphocytes adapt to any tissue, just like I did when I came to San Diego. First, I bought an American phone. In Germany I tried to speak German. They are different types of adaptations that allow you to live in one place or another,” he explains. The same applies to T lymphocytes, which develop different strategies depending on whether they are anchored in the intestine, in the lungs or in another organ.
Reina’s team focused on the intestine and analyzed the T lymphocytes resident there one by one – cells measuring just a few thousandths of a millimeter. Their results show that these intestinal white blood cells strengthened the machinery that synthesizes cholesterol, a fat-like substance that is essential for cell function. However, in their experiments, a diet high in cholesterol reduced the performance of T lymphocytes instead of increasing it. Reina explains that when these cells detect excess cholesterol, they stop producing excess cholesterol, just as a person would stop cooking if they were given free meals at home.
The researchers then focused on an intermediate product of this cholesterol formation: coenzyme Q, a molecule necessary for energy production in the mitochondria, the cell’s batteries. “We saw that the T lymphocytes cranked up the cholesterol production machinery, but not to make cholesterol, but to produce coenzyme Q, which increases the ability to produce energy,” explains Reina. His group even identified an existing drug that increases coenzyme Q production and extends survival in mice with cancer: Zaragoza acid A, a natural product isolated three decades ago in a fungal culture obtained from a water sample from the Jalon River in Zaragoza . Spain.
The biochemist is optimistic. “The adaptations we discovered can be applied quite well to cancer therapies in general, as they do not only take place in the intestine. They could be useful against colon cancer and melanoma, and probably other types of tumors as well. Now, for example, we need to study the adaptations of the lungs to see if we can improve the treatment of lung cancer. The same goes for the liver and so on,” Reina reflects.
The researcher mentions another important aspect: more than 200 million people in the world take statins, a drug that lowers blood cholesterol levels. “Statins block cholesterol metabolism and could therefore be toxic or harmful to T cells in the intestine. We need to do more research to find out what the real effects are on humans. We don’t want to be alarmists; We’re just saying that this needs to be analyzed more closely,” he says. However, Reina emphasizes that the health benefits of taking statins are undisputed: Epidemiological studies have found no increase in cancer cases among people taking statins.
Immunologist Santos Mañes from the Spanish National Center for Biotechnology considers the new study to be very relevant. “The fundamental importance of this work is that it shows that a resident T cell in the small intestine is not the same as a resident T cell in the liver or kidney,” he says. “The tissue environment in which these cells are located is their metabolic program. And the conditioning of the metabolic program influences their functionality,” he explains.
Mañes also imagines the applications. “Intestinal resident memory T cells are highly dependent on coenzyme Q, so it is clear that treatments that successfully increase the synthesis of coenzyme Q would improve their function and therefore play a more important antitumor role.” I have points. And he warns: “Extrapolation shows that a diet rich in cholesterol could promote the development of intestinal tumors by inhibiting these cells.”
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