In a normal immune response, killer T cells are activated by antigen stimulation and selectively eliminate only virus-infected cells, thereby controlling viral replication and promoting the patient’s rapid recovery. However, when killer T cells are nonspecifically overactivated by interleukin-15, they may randomly attack normal cells as well, causing excessive tissue damage and leading to severe disease. Future research may identify diseases in which such nonspecific hyperimmune responses occur, making it possible to develop new drugs to control them. Credit: The Korea Advanced Institute of Science and Technology (KAIST)

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.

The 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 increased 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, now published in the journal Immunity, 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.

Professor Eui-Cheol Shin explained, “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.”

More information: Hoyoung Lee et al, TCR signaling via NFATc1 constrains IL-15-induced bystander activation of human memory CD8+ T cells, Immunity (2025). DOI: 10.1016/j.immuni.2025.10.002

Citation: Immune overreactions explained: How killer T cells turn against the body (2025, November 6) retrieved 6 November 2025 from https://medicalxpress.com/news/2025-11-immune-overreactions-killer-cells-body.html

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