Many people do not know it, but inside their chest, between the upper tips of their lungs, there is a small gland similar to a thyme flower: the thymus, weighing barely one ounce. White blood cells — the defenses of the human body — are formed inside the bones, but some travel to the thymus to mature into cytotoxic T lymphocytes, the true killers in the immune system, even capable of destroying cancer cells. Now, a team led by Spanish biochemist Miguel Reina has found a way to strengthen these soldiers and improve 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. When a virus attacks, say, the intestine, these white blood cells go there and kill the infected cells. Once the problem is solved, the T lymphocytes remain in the organ for decades as permanent security guards. This is called tissue-resident memory. Reina uses his own life as an example to explain the phenomenon. The Barcelona-born biochemist does his research at the University of California, in San Diego, in the United States, and a decade ago, he briefly passed through a German center. “Lymphocytes adapt to each tissue, just like I did when I came to San Diego. For starters, I bought an American phone. In Germany, I tried to speak German. They are different types of adaptations that let you live in one place or another,” he explains. The same thing occurs with T lymphocytes, which develop different strategies depending on whether they are attached to the intestine, the lung or any another organ.
Reina’s team focused on the intestine, analyzing one by one the resident T lymphocytes — cells of just a few thousandths of a millimeter. Their results show that these intestinal white blood cells have strengthened the machinery that synthesizes cholesterol, a substance similar to fat and essential for cell function. However, in their experiments, a high-cholesterol diet reduced the efficiency of T-lymphocytes, rather than increasing it. Reina explains that if these cells detect excess cholesterol, they stop producing it, just as a person would stop cooking if they received free meals at home.
The researchers then focused on an intermediate product of this creation of cholesterol: coenzyme Q, a molecule necessary to generate energy in the mitochondria, the cell’s batteries. “What we saw is that the T lymphocytes enhanced the cholesterol production machinery, but not to make cholesterol, rather to make coenzyme Q, which increases the ability to generate energy,” Reina explains. His group even identified an existing drug that increases the production of coenzyme Q and prolongs the survival of mice with cancer: zaragozic 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 that we found translate quite well to cancer therapies in general, because they don’t just happen in the gut. They could be useful against colon cancer and melanoma, and probably other types of tumors as well. Now we need to study, for example, the adaptations to the lung, to see if we can improve treatments for lung cancer. The same with the liver, and so on,” reflects Reina.
The researcher mentions another key aspect: more than 200 million people in the world take statins, a drug that lowers the level of cholesterol in the blood. “Statins block cholesterol metabolism, so they could be toxic or harmful to the T cells in the intestine. We need to do more research to find out what the real repercussions are in humans. We don’t want to be alarmists; we’re just saying that this must be analyzed in greater detail,” he says. Reina, however, emphasizes that the health benefit of taking statins is indisputable: epidemiological studies have not detected an increase in cancer cases in people who take statins.
Immunologist Santos Mañes, from the Spanish National Center for Biotechnology, believes that the new study is 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 conditions their metabolic program. And conditioning the metabolic program conditions their functionality,” he explains.
Mañes also envision the applications. “Gut-resident memory T cells are highly dependent on coenzyme Q, so it is clear that treatments that succeed in increasing coenzyme Q synthesis would enhance their function and, therefore, have a more prominent antitumor role.” he points out. And he issues a warning: “Extrapolating, it could be inferred that a diet rich in cholesterol could favor the generation of intestinal tumors by inhibiting these cells.”
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