Many people don’t know that in their chest, between the upper tips of their lungs, there is a small gland that resembles the flower of thyme: the thymus, which weighs just under 30 grams. 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, which can even destroy cancer cells. A team led by Spanish biochemist Miguel Reina has now found a way to strengthen these soldiers and improve their immunity to tumors and infections. Their discovery will be published this Wednesday in the journal Nature, the world’s leading scientific journal.
T lymphocytes leave the thymus gland, i.e., the T, and circulate through the blood. For example, when a virus attacks the gut, these white blood cells come in and kill the infected cells. Once the problem is solved, the T-lymphocytes remain in the service organ as perpetual security guards for decades. It is called tissue-resident memory. Reina, born 32 years ago in Barcelona, explains the phenomenon using his own life as an example. The biochemist conducts research at the University of California, San Diego, USA. And a decade ago, he briefly went through a German center. “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 concentrated on the intestine and individually analyzed the T-lymphocytes located there, cells only a few thousandths of a millimeter thick. Their results show that these intestinal white blood cells have improved the machinery for synthesizing cholesterol, a fat-like substance essential for cell function. However, in their experiments, a high-cholesterol diet reduced the performance of T lymphocytes instead of increasing them. Reina explains that when these cells detect excess cholesterol, they stop producing excess cholesterol, just as a person would stop cooking if they brought home-cooked meals for free.
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 actual batteries. “We saw that the T lymphocytes augmented the cholesterol production machinery, but not to make cholesterol but to produce coenzyme Q, which increases the ability to produce energy,” Reina points out. His group has even identified an existing drug that increases coenzyme Q production and prolongs the survival of mice with cancer. It is Zaragoza acid A, a natural product isolated three decades ago in a fungal culture obtained from a water sample taken from the Jalón river in Zaragoza.
The biochemist is optimistic. “The adaptations we found translate quite well to cancer therapies in general, since they don’t just take place in the gut. They could be useful against colon cancer and melanoma, and probably against other types of tumors as well. Now, for example, adaptations in the lungs need to be studied to see if we can improve the treatment of lung cancer. And the same goes for the liver, etc.”, Reina reflects.
The investigator notices another key. More than 200 million people around the world take statins, a type of drug used to lower blood cholesterol levels. “Statins block cholesterol metabolism and could therefore be toxic or harmful to T-cells in the gut. We need to do more research to find out what effects it actually has on humans. We don’t want to alarm; we’re just saying that this needs to be analyzed more closely,” he stresses. However, Reina emphasizes that the health benefits of taking statins are undeniable. Epidemiological studies have found no increase in cancer cases among people taking statins.
The immunologist Santos Maes considers the new study to be highly 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,” says Maes of the National Center for Biotechnology in Madrid. “The tissue environment in which these cells are located determines their metabolic program. And the conditioning of the metabolic program determines its functionality,” he summarizes.
Maes also feels the applications “Gut resident memory T cells are highly dependent on coenzyme Q, so it is clear that treatments that increase coenzyme Q synthesis would improve their function and therefore play a more important antitumor role,” it says. And he warns: “Extrapolated, it can be deduced that a high-cholesterol diet could promote the development of intestinal tumors by inhibiting these cells.”
