In recent years, it has become clear that our immune system not only protects against infection but also plays a role in a variety of diseases, including cancer, allergies, stroke, and Alzheimer's disease. In cancer treatment, immunotherapy has attracted a great deal of attention because the patient's immune system can eradicate tumors. However, there are still limitations to cancer immunotherapy; T cells, the major immune cells that kill cancer cells, become exhausted by fighting cancer cells and eventually cease to function.
The underlying mechanism of T cell exhaustion has long been a mystery. However, a recent breakthrough could overcome one of these limitations. Through research on laboratory mice, Professor Akihiko Yoshimura and his colleagues in the Department of Microbiology and Immunology at Keio University School of Medicine have revealed for the first time the mechanism by which T cells become exhausted and cease to function inside cancerous tissue. The group discovered the gene NR4A, which is responsible for T cell exhaustion, and demonstrated that cancer treatment could be more effective by inhibiting NR4A.
“The cells of the immune system uniquely regulate the body’s immune responses, much like applying accelerators and brakes when driving a car. Immunological research is merely the investigation into understanding the mechanism of these accelerators and brakes.”
When a virus invades our body or when cancer cells emerge, cells of the immune system spring into action to prevent the intrusion of the virus or to attack and destroy the infected cells or cancer cells. However, if these immune responses are too strong, the immune system may attack the body itself, leading to autoimmune disorders or a condition known as a cytokine storm, which has been in the news recently due to its prevalence in severe COVID-19 infections.
“The immune system distinguishes between the ‘self’ (one's own body) and the ‘non-self’ (foreign substances present in the body) and works to eliminate these foreign substances. But what would happen if it attacked all foreign or ‘non-self’ substances? There’s no doubt that humans would not be able to survive. For example, food is a foreign substance, yet we need to eat it every day to survive. And when a woman becomes pregnant, her body nurtures the baby growing in the womb , even though half of the baby is more or less a stranger to the mother’s body. If our immune system attacked the fetus, the human species would not survive.
This regulation of the immune system and allowance of foreign substances without regarding them as intrusive is called immune tolerance.
“Immune tolerance is essentially applying the brakes of the immune system. These brakes are what allow us to eat and procreate. But an overactive immune system can lead to allergies, miscarriages, autoimmune diseases, cytokine storms, and other issues.”
Professor Yoshimura and his colleagues found that NR4A is the key to both immune tolerance and the mechanism by which T cells are exhausted and rendered ineffective in the fight against cancer cells. "NR4A is, so to speak, the main controller of the brakes of the immune system," says Professor Yoshimura.
His findings led to research on regulatory T cells, and in 2013, Professor Yoshimura and his colleagues published their discovery of the gene NR4A and its role in regulating T cells in "Nature Immunology".
“We wanted to clarify what molecules generate regulatory T cells and how regulatory T cells function as regulators of the immune system at the molecular level. My approach to research style has always been focused on the molecular aspects. After moving my lab to Keio, we discovered that NR4A was the molecule we had been looking for for years —that is, the molecule that creates regulatory T cells.”
Having identified NR4A as essential for the creation of regulatory T cells, Professor Yoshimura considers it to be the fundamental molecule among the many molecular brakes. The group’s research also showed that activation of NR4A in mice can make T cells become regulatory T cells, which have never been shown to differentiate by other methods.
“Allergic diseases such as hay fever and asthma, and autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease are caused by excessive immune responses, and regulatory T cells mediate these responses. NR4A creates these regulatory T cells, and it is NR4A that is responsible for controlling regulatory T cell-mediated immune tolerance in the first place.”
So, does the inhibition of NR4A, which governs exhaustion, serve to rejuvenate T cells?
“We don’t fully understand that yet. Our goal is to rejuvenate the completely exhausted and inactive T cells. And in fact, we are having success rejuvenating T cells in the test tube.”
CAR T cell therapy is currently attracting attention as a treatment for blood cancers. In this therapy, T cells are harvested from the patient's blood, and a gene called CAR, which recognizes cancer, is introduced into the T cells in a test tube, after which they are returned to the patient’s body.
“CAR T cell therapy works well in children and young adults with high levels of healthy immune cells. This is because they have many healthy, young T cells that have just been born, and by reintroducing them to the body with improved cancer recognition, they are effective in fighting cancer. However, in the elderly, immune cells are also aging, and their CAR T cells are not as effective. Although the terms ‘aging’ and ‘exhaustion’ are different, the underlying mechanism is similar. If you try to use aged T cells, they quickly become exhausted after introducing the CAR gene.”
Professor Yoshimura and his colleagues are conducting experiments to restore aged T cells to their young state.
“Although not exactly the same as the original young cells, we are now able to confirm that exhausted cells can be rejuvenated in vitro. We have succeeded in rejuvenating T cells by adding several external factors such as cytokines and growth factors. Although we have yet to successfully rejuvenate T cells inside the human body, we believe that treatment will become even more effective if we can rejuvenate them as they proliferate outside the body in combination with CAR T cell therapy.”
Since then, Professor Yoshimura and his colleagues have continued their research and explained the inflammatory process after a stroke, focusing on macrophages of the immune system.
“This process occurs when tissue breaks down and dies anywhere in the body, not only brain tissue, but also in the lungs and kidneys, and wherever cancer grows. Stroke, caused by a clogged blood vessel, is probably one of the most common causes of this kind of damage. An immune response occurs even when physical trauma is sustained in a car accident. What happens is that when the body sustains a wound, the tissue dies, and immune cells gather in that location.”
“We have found that this has both beneficial and harmful effects. In the acute phase, immediately after stroke onset, inflammatory macrophages infiltrate the stroke site, recognize dead cell material, and release inflammatory cytokines to promote inflammation. This process promotes neuronal death. The inflammatory response then subsides in approximately one week, after which macrophages switch to having tissue-repairing properties to remove inflammatory substances and further promote regeneration of the nervous system.”
Furthermore, Professor Yoshimura and his colleagues found that in the chronic phase beginning more than two weeks after the stroke onset, regulatory T cells accumulate in large numbers in the brain and play an essential role in improving neurological symptoms. The detailed mechanism of this process was published in Nature in 2019. It has become clear that when a stroke or other condition results in physical tissue damage, the immune system plays an important role in tissue damage and repair, including in the brain.
So Professor Yoshimura reveals his secret to success and how he became an immunology researcher unlocking the mysteries of the immune system.
“Stroke and cancer may seem unrelated, but in my mind, they are connected by immunity. We now know that immunity is deeply connected to almost every field of medicine. Moving forward, I hope to conduct further research in areas where immunity may have traditionally been overlooked in hopes of shedding more light on the hidden world of immunity.”
Professor Yoshimura graduated from the Faculty of Science at Kyoto University in 1981. He obtained a master’s degree from the Graduate School of Science at Kyoto University in 1983 and received his Ph.D. in 1985. After working at the Oita Medical University Department of Chemistry, he became an assistant professor at the Cancer Research Institute at Kagoshima University’s School of Medicine in 1987. After training as a postdoctoral fellow at the Massachusetts Institute of Technology, he became an associate professor at the Kagoshima University School of Medicine Cancer Research Institute in 1989 before serving as a professor at the Kurume University Institute of Life Science in 1995 and a professor at the Kyushu University Medical Institute of Bioregulation in 2001. He assumed his current position in 2008. In 2021, he was awarded the Uehara Prize and Japan’s Medal of Honor with Purple Ribbon.