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KAIST Uncovers the Mechanism Behind Overactive Immune Cells
<(From Right) Professor Eui-Cheol Shin, Ph.D candidate So-Young Kim, Professor Su-Hyung Park, Professor Hyuk Soo Eun, Dr. Hoyoung Lee>
“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.
<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>
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.
Professor Eui-Cheol Shin explained that, “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.”
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.
Title: “TCR signaling via NFATc1 constrains IL-15-induced bystander activation of human memory CD8⁺ T cells”, DOI: doi.org/10.1016/j.immuni.2025.10.002
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).
2025.11.06 View 1085 -
KAIST Professors Participate in Mastering Immunity 2025 Singapore Summit
<2025 Global Infectious Diseases Summit>
KAIST is proud to announce the participation of Professors Eui-Cheol Shin and Jeong Seok Lee in the Mastering Immunity 2025: Global Infectious Diseases Summit, held on 1–2 September 2025 in Singapore. This international symposium brought together leading experts in immunology to discuss the latest advancements in infectious disease research, vaccine development, and immune response characterization.
At the summit, Professor Eui-Cheol Shin contributed as a speaker, sharing insights from his groundbreaking research in immunology, while Professor Jeong Seok Lee also presented on his latest work in the field. Professor Eui-Cheol Shin joined a panel discussion alongside other distinguished global experts, highlighting the importance of collaboration in addressing pressing infectious disease challenges.
The summit was organized by ProImmune, an international life-science company specializing in innovative immunology solutions. Through cutting-edge technologies, including Ankyron® target-binding reagents, Pro5® MHC Class I Pentamers, ProT2® MHC Class II Tetramers as well as immunology-based assays such as REVEAL® MHC Binding Assays and ProPresent® Antigen Presentation Assays are accelerating this vital research. ProImmune supports researchers worldwide in understanding immune responses and accelerating the development of vaccines and immunotherapies.
<Presentation at the Summit>
KAIST celebrates the contributions of Professors Shin and Lee in representing Korean science on the global stage and advancing the understanding of infectious diseases.
For more information about the Mastering Immunity 2025 summit and to view the recorded talks, visit: https://www.proimmune.com/conference-videos
2025.09.13 View 1119 -
A Mathematical Model Shows High Viral Transmissions Reduce the Progression Rates for Severe Covid-19
The model suggests a clue as to when a pandemic will turn into an endemic
A mathematical model demonstrated that high transmission rates among highly vaccinated populations of COVID-19 ultimately reduce the numbers of severe cases. This model suggests a clue as to when this pandemic will turn into an endemic.
With the future of the pandemic remaining uncertain, a research team of mathematicians and medical scientists analyzed a mathematical model that may predict how the changing transmission rate of COVID-19 would affect the settlement process of the virus as a mild respiratory virus.
The team led by Professor Jae Kyoung Kim from the Department of Mathematical Science and Professor Eui-Cheol Shin from the Graduate School of Medical Science and Engineering used a new approach by dividing the human immune responses to SARS-CoV-2 into a shorter-term neutralizing antibody response and a longer-term T-cell immune response, and applying them each to a mathematical model. Additionally, the analysis was based on the fact that although breakthrough infection may occur frequently, the immune response of the patient will be boosted after recovery from each breakthrough infection.
The results showed that in an environment with a high vaccination rate, although COVID-19 cases may rise temporarily when the transmission rate increases, the ratio of critical cases would ultimately decline, thereby decreasing the total number of critical cases and in fact settling COVID-19 as a mild respiratory disease more quickly.
Conditions in which the number of cases may spike include relaxing social distancing measures or the rise of variants with higher transmission rates like the Omicron variant. This research did not take the less virulent characteristic of the Omicron variant into account but focused on the results of its high transmission rate, thereby predicting what may happen in the process of the endemic transition of COVID-19.
The research team pointed out the limitations of their mathematical model, such as the lack of consideration for age or patients with underlying diseases, and explained that the results of this study must be applied with care when compared against high-risk groups. Additionally, as medical systems may collapse when the number of cases rises sharply, this study must be interpreted with prudence and applied accordingly. The research team therefore emphasized that for policies that encourage a step-wise return to normality to succeed, the sustainable maintenance of public health systems is indispensable.
Professor Kim said, “We have drawn a counter-intuitive conclusion amid the unpredictable pandemic through an adequate mathematical model,” asserting the importance of applying mathematical models to medical research.
Professor Shin said, “Although the Omicron variant has become the dominant strain and the number of cases is rising rapidly in South Korea, it is important to use scientific approaches to predict the future and apply them to policies rather than fearing the current situation.”
The results of the research were published on medRxiv.org on February 11, under the title “Increasing viral transmission paradoxically reduces progression rates to severe COVID-19 during endemic transition.”
This research was funded by the Institute of Basic Science, the Korea Health Industry Development Institute, and the National Research Foundation of Korea.
-PublicationHyukpyo Hong, Ji Yun Noh, Hyojung Lee, Sunhwa Choi, Boseung Choi, Jae Kyung Kim, Eui-Cheol Shin, “Increasing viral transmission paradoxically reduces progression rates to
severe COVID-19 during endemic transition,” medRxiv, February 9, 2022 (doi.org/10.1101/2022.02.09.22270633)
-ProfileProfessor Jae Kyung KimDepartment of Mathematical SciencesKAIST
Professor Eui-Cheol ShinGraduate School of Medical Science and EngineeringKAIST
2022.02.22 View 15631 -
Study of T Cells from COVID-19 Convalescents Guides Vaccine Strategies
Researchers confirm that most COVID-19 patients in their convalescent stage carry stem cell-like memory T cells for months
A KAIST immunology research team found that most convalescent patients of COVID-19 develop and maintain T cell memory for over 10 months regardless of the severity of their symptoms. In addition, memory T cells proliferate rapidly after encountering their cognate antigen and accomplish their multifunctional roles. This study provides new insights for effective vaccine strategies against COVID-19, considering the self-renewal capacity and multipotency of memory T cells.
COVID-19 is a disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. When patients recover from COVID-19, SARS-CoV-2-specific adaptive immune memory is developed. The adaptive immune system consists of two principal components: B cells that produce antibodies and T cells that eliminate infected cells. The current results suggest that the protective immune function of memory T cells will be implemented upon re-exposure to SARS-CoV-2.
Recently, the role of memory T cells against SARS-CoV-2 has been gaining attention as neutralizing antibodies wane after recovery. Although memory T cells cannot prevent the infection itself, they play a central role in preventing the severe progression of COVID-19. However, the longevity and functional maintenance of SARS-CoV-2-specific memory T cells remain unknown.
Professor Eui-Cheol Shin and his collaborators investigated the characteristics and functions of stem cell-like memory T cells, which are expected to play a crucial role in long-term immunity. Researchers analyzed the generation of stem cell-like memory T cells and multi-cytokine producing polyfunctional memory T cells, using cutting-edge immunological techniques.
This research is significant in that revealing the long-term immunity of COVID-19 convalescent patients provides an indicator regarding the long-term persistence of T cell immunity, one of the main goals of future vaccine development, as well as evaluating the long-term efficacy of currently available COVID-19 vaccines.
The research team is presently conducting a follow-up study to identify the memory T cell formation and functional characteristics of those who received COVID-19 vaccines, and to understand the immunological effect of COVID-19 vaccines by comparing the characteristics of memory T cells from vaccinated individuals with those of COVID-19 convalescent patients.
PhD candidate Jae Hyung Jung and Dr. Min-Seok Rha, a clinical fellow at Yonsei Severance Hospital, who led the study together explained, “Our analysis will enhance the understanding of COVID-19 immunity and establish an index for COVID-19 vaccine-induced memory T cells.”
“This study is the world’s longest longitudinal study on differentiation and functions of memory T cells among COVID-19 convalescent patients. The research on the temporal dynamics of immune responses has laid the groundwork for building a strategy for next-generation vaccine development,” Professor Shin added. This work was supported by the Samsung Science and Technology Foundation and KAIST, and was published in Nature Communications on June 30.
-Publication:
Jung, J.H., Rha, MS., Sa, M. et al. SARS-CoV-2-specific T cell memory is sustained in COVID-19 convalescent patients for 10 months with successful development of stem cell-like memory T cells. Nat Communications 12, 4043 (2021). https://doi.org/10.1038/s41467-021-24377-1
-Profile:
Professor Eui-Cheol Shin
Laboratory of Immunology & Infectious Diseases (http://liid.kaist.ac.kr/)
Graduate School of Medical Science and Engineering
KAIST
2021.07.05 View 19478 -
Study Finds Interferon Triggers Inflammation in Severe COVID-19
KAIST medical scientists and their colleagues confirmed that the type I interferon response plays a pivotal role in exacerbating inflammation in severe COVID-19 cases. Severe COVID-19 has been shown to be caused by a hyper-inflammatory response. Particularly, inflammatory cytokines secreted by classical monocytes and macrophages are believed to play a crucial role in the severe progression of COVID-19.
A new single-cell RNA sequencing analysis of more than 59,000 cells from three different patient cohorts provided a detailed look at patients’ immune responses in severe cases of COVID-19. The results suggest that patients with severe cases of COVID-19 experience increased regulation of the type I interferon (IFN-I) inflammation-triggering pathway, a signature that the researchers also observed in patients hospitalized with severe cases of influenza.
Their findings suggest that anti-inflammatory treatment strategies for COVID-19 should also be aimed toward the IFN-I signaling pathway, in addition to targeting inflammatory molecules such as TNF, IL-1, and IL-6, which have been associated with COVID-19.
The research team under Professor Eui-Cheol Shin from the Graduate School of Medical Science and Engineering sequenced the RNA from a total of 59,572 blood cells obtained from four healthy donors, eight patients with mild or severe COVID-19, and five patients with severe influenza.
By comparison, patients with severe cases of influenza showed increased expression of various IFN-stimulated genes, but did not experience TNF/IL-1 responses as seen in COVID-19 patients. Unlike the flu cohort, patients in the severe COVID-19 cohort exhibited the IFN-I signature concurrently with TNF/IL-1-driven inflammation – a combination also not seen in patients with milder cases of COVID-19.
Their result, along with past mouse studies that highlight how the timing of IFN-I expression is critical to determining the outcome of SARS, support targeting IFN-I as a potential treatment strategy for severe COVID-19.
Professor Shin said, “This research provides insights for designing therapeutic options for COVID-19 by investigating very closely how the immune cells of COVDI-19 patients develop. We will continue to conduct research on novel therapeutic immune mechanisms and target therapeutic anti-inflammatory medication to improve the survival of severe COVID-19 patients.”
This study, conducted in collaboration with Severance Hospital at Yonsei University, Asan Medical Center, and Chungbuk National University, was featured in Science Immunology on July 10. This work was funded by Samsung Science and Technology Foundation and SUHF Fellowship.
-PublicationScience Immunology 10 Jul 2020:Vol. 5, Issue 49, eabd1554DOI: 10.1126/sciimmunol.abd1554
-ProfileProfessorEui-Cheol ShinGraduate School of Medical Science and EngineeringLaboratory of Immunology & Infectious Diseases (http://liid.kaist.ac.kr/)euicheols@kaist.ac.krKAIST
2020.07.14 View 11280 -
New Members of KAST and Y-KAST 2019
(Professor Eui-Cheol Shin from the Graduate School of Medical Science and Engineering)
Professor Eui-Cheol Shin from the Graduate School of Medical Science and Engineering became a new fellow of the Korean Academy of Science and Technology (KAST) along with 25 other scientists in Korea. He is one of the top virus immunologists in Korea and has published a review article in Nature Reviews Immunology.
Meanwhile KAST selected and announced 26 young scientists under the age 43 who have shown great potential and the creativity to carry out next-generation research. The list of Y-KAST (Young Korean Academy of Science and Technology) includes six KAIST professors: Professor Ji Oon Lee from the Department of Mathematical Sciences, Professor Mi Hee Lim from the Department of Chemistry, Professor Shin-Hyun Kim from the Department of Chemical and Biomolecular Engineering, Professor Jung-Ryul Lee from the Department of Aerospace Engineering, Professor Hyunjoo Jenny Lee from the School of Electrical Engineering, and Professor Yeon Sik Jung from the Department of Materials Science and Engineering.
KAST conferred their fellowships and Y-KAST membership during the New Year Reception.
2019.01.22 View 13197