Immune cells are commonly known for helping to protect health by fighting viruses. However, like an overheated engine, overactivated immune cells can indiscriminately destroy both viruses and normal cells. A Korean research team has identified the core principle that controls the activation process of immune cells, offering a clue for the development of treatments for immune disorders.
KAIST announced on November 5 that the research team led by Professors Shin Euichul and Park Suhyung of the Graduate School of Medical Science and Engineering, in collaboration with Professor Eun Hyuksu of Chungnam National University College of Medicine, has identified the cause of non-specific activation of "killer T cells (CD8+ T cells)" and proposed a new therapeutic strategy to regulate this process.
(From right) Professor Shin Eui-cheol of KAIST, So-young Kim, KAIST PhD candidate, Professor Park Su-hyung of KAIST, Professor Eun Hyuk-su of Chungnam National University College of Medicine, (top) Ho-young Lee, KAIST PhD. Provided by KAIST
Normally, killer T cells selectively eliminate only infected cells, thereby suppressing the spread of viruses. However, when the response becomes excessive, they may attack even uninfected normal cells, causing inflammation and tissue damage. Such "excessive immune responses" can lead to severe viral diseases or autoimmune disorders.
In 2018, the joint research team was the first in the world to discover that killer T cells non-specifically activated by cytokines can randomly attack any cell, a phenomenon they termed "non-specific T cell activation." This follow-up study focused on uncovering the molecular mechanism behind the non-specific activation of killer T cells.
During the research, the team focused on a substance called "interleukin-15 (IL-15)" among various cytokines. Experimental results showed that IL-15 can abnormally excite killer T cells, causing them to attack uninfected cells. However, in the presence of antigenic stimulation such as viral infection, IL-15 was found to suppress this excessive reaction.
The team also newly discovered that this suppressive effect occurs when changes in intracellular calcium levels activate a protein called calcineurin, which then signals a regulatory protein called NFAT to control the behavior of killer T cells. The calcineurin-NFAT pathway, activated by IL-15 signaling inside the cell, effectively acts as a brake.
The joint research team further confirmed that some immunosuppressants, by blocking the calcineurin pathway, may fail to suppress immunity and instead promote excessive activation of killer T cells via IL-15 under certain conditions. This indicates that not all immunosuppressants function in the same way, and that medications should be carefully selected based on the patient's immune response profile.
Through gene expression analysis, the research team identified a set of genes (markers) that increase only in killer T cells abnormally activated by IL-15, and confirmed that these markers are also significantly elevated in the killer T cells of patients with acute hepatitis A. This suggests the potential for these markers to be used in disease diagnosis.
This study provides important clues for understanding the causes of various immune diseases, including severe viral infections, chronic inflammatory diseases, autoimmune disorders, and organ transplant rejection. It also confirms the potential for developing new immunomodulatory therapies targeting IL-15 signaling.
Professor Shin stated, "Killer T cells in our body are not simply defenders but can become 'non-specific attackers' depending on the inflammatory environment. By precisely regulating such abnormal activation, we may be able to develop new treatments for intractable immune diseases."
This research was jointly conducted by Dr. Lee Hoyoung and PhD candidate Kim Soyoung of the Graduate School of Medical Science and Engineering as co-first authors. The findings were recently published in the international journal 'Immunity.'
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