A domestic research team has identified a key principle that can control the activation process of runaway killer T cells. The findings are expected to offer clues for developing therapeutics to regulate excessive immune responses in immune disorders.
A research team led by Professors Shin Eui-cheol and Park Soo-hyung at the Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), said on the 5th that, in joint research with Professor Eun Hyuk-soo of Chungnam National University College of Medicine, they identified the molecular cause of nonspecific activation of killer T cells and proposed a new treatment strategy to control it. The findings were published in the international journal Immunology (Immunity) on Oct. 31 (local time).
Killer T cells (CD8+ T cells) are immune cells that selectively remove infected cells to curb the spread of viruses, but when their response becomes excessive, they can attack even uninfected normal cells, causing inflammation and tissue damage. Such excessive immune responses can lead to severe viral diseases or autoimmune disorders.
In this study, the team focused on a protein called cytokine that immune cells secrete, specifically a substance called interleukin-15 (IL-15). In 2018, the team was the first in the world to find that killer T cells nonspecifically activated by cytokines attack any cells at random, and they termed this nonspecific T cell activation. This follow-up study elucidates the molecular mechanism of such nonspecific activation.
The experiments showed that IL-15 abnormally excites killer T cells, prompting them to attack even uninfected cells, but conversely, when there is an antigenic stimulus such as a viral infection, it suppresses such overreactions.
The team also newly found that when intracellular calcium levels change, a protein called calcineurin is activated, and this signal moves a regulatory protein called NFAT to control the behavior of killer T cells. In other words, the intracellular calcineurin–NFAT pathway activated by IL-15 signaling acts as a brake.
The researchers further confirmed that some immunosuppressants block this calcineurin pathway and, instead of suppressing immunity, can actually promote excessive IL-15–driven activation of killer T cells in certain situations. This means immunosuppressants do not all act the same and that drugs should be chosen carefully based on a patient's immune response profile.
Through gene expression analysis, the team identified a gene set (marker) that increases only in killer T cells abnormally activated by IL-15 and confirmed that this marker is markedly elevated in the killer T cells of patients with acute hepatitis A. The marker can be used for disease diagnosis.
Professor Shin Eui-cheol said, "Killer T cells in our body are not simply defenders; the study shows they can turn into 'nonspecific attackers' depending on the inflammatory environment," adding, "If we precisely control this abnormal activation, we may be able to develop new treatments for intractable immune diseases."
References
Immunity (2025), DOI: https://doi.org/10.1016/j.immuni.2025.10.002