Study identifies molecular brake that controls overactive killer T cells

"Why do immune cells that are supposed to eliminate viruses suddenly turn against our own body?"

There are instances where killer T cells—which are meant to precisely remove virus-infected cells—malfunction like overheated engines, attacking even healthy cells and damaging tissues. A KAIST research team has now identified the key mechanism that regulates this excessive activation of killer T cells, offering new insights into controlling immune overreactions and developing therapies for immune-related diseases.

KAIST (President Kwang Hyung Lee) announced on November 5 that a research team led by Professors Eui-Cheol Shin and Su-Hyung Park from the Graduate School of Medical Science and Engineering, in collaboration with Professor Hyuk Soo Eun from Chungnam National University College of Medicine, has uncovered the molecular basis of nonspecific activation in killer T cells and proposed a new therapeutic strategy to control it.

Killer T cells (CD8⁺ T cells) selectively eliminate infected cells to prevent viral spread. However, when excessively activated, they can attack uninfected cells, causing inflammation and tissue damage. Such overactive immune responses can lead to severe viral infections and autoimmune diseases.

In 2018, Professor Shin's team was the first in the world to discover that killer T cells can be nonspecifically activated by cytokines and randomly attack host cells—a phenomenon they termed "bystander activation of T cells". The current study builds on that discovery by revealing the molecular mechanism driving this abnormal process.

The team focused on a cytokine called interleukin-15 (IL-15). Experiments showed that IL-15 can abnormally excite killer T cells by a bystander activation mechanism, causing them to attack uninfected host cells. However, when there is a concurrent antigen-specific stimulation, IL-15-induced bystander activation is suppressed.

The researchers further identified that this suppression occurs through an intracellular signaling process. When the concentration of calcium ions (Ca²⁺) changes, a protein called calcineurin activates, which in turn triggers a regulatory protein known as NFAT, suppressing IL-15-induced bystander activation of killer T cells. In other words, the calcineurin-NFAT pathway activated by antigen stimulation acts as a brake on overactivation by a bystander mechanism.

The team also discovered that some immunosuppressants, which are known to block the calcineurin pathway, may not always suppress immune responses—in certain contexts, they can instead promote IL-15-induced bystander activation of killer T cells. This finding underscores that not all immunosuppressants work the same way and that treatments must be carefully tailored to each patient's immune response.

Through gene expression analysis, the researchers identified a gene set that increase only in abnormally activated killer T cells induced by IL-15 as markers. They further confirmed that these same markers were elevated in bystander killer T cells from patients with acute hepatitis A, suggesting that the markers could be used for disease diagnosis.

This study provides crucial clues for understanding the pathogenesis of various immune-related diseases, including severe viral infections, chronic inflammatory disorders, autoimmune diseases, and organ transplant rejection. It also paves the way for developing novel immunoregulatory therapies targeting IL-15 signaling.

This study shows that killer T cells are not merely defenders—they can transform into 'nonspecific attackers' depending on the inflammatory environment. By precisely regulating this abnormal activation, we may be able to develop new treatments for intractable immune diseases."

Professor Eui-Cheol Shin

This research was published in the journal Immunity on October 31, with Dr. Hoyoung Lee and Ph.D. candidate So-Young Kim as co-first authors.

The study was supported by the National Research Foundation of Korea (NRF), the Korea Health Industry Development Institute (KHIDI), and the Institute for Basic Science (IBS).