GIST Identifies Mechanism of T Cell Immune-Regulating Protein Cdc42 for the First Time

(From left) Professor Changdeok Jeon of the Department of Life Sciences, Wonchang Seo, PhD student.

The Gwangju Institute of Science and Technology (GIST) announced on the 29th that a research team led by Professor Jeon Changdeok from the Department of Life Sciences has identified the role of the key protein Cdc42 in the formation of microvilli on the surface of T cells and in regulating immune function, suggesting the potential for the development of new immunotherapeutics.

T cells are core components of the immune system that recognize and defend against external pathogens (antigens) such as viruses and bacteria. In particular, the microvilli densely covering the surface of T cells play a crucial role in detecting traces of pathogens and inducing immune responses.

Previously, microvilli on T cells were thought to play only a passive role in detecting external signals (antigens). However, through this study, the research team has, for the first time in the world at the molecular level, demonstrated that microvilli act as active "immune antennas" responsible not only for antigen recognition, but also for immune synapse formation, amplification, and transmission of immune signals.

The research team confirmed that even after T cells come into contact with antigen-presenting cells (APCs), some microvilli detach from the T cell and remain on the surface of the APC, continuously transmitting signals. This significant discovery shows that, much like a "USB memory" storing information, there is a new pathway by which microvilli can sustain immune responses over the long term even after brief contact.

However, it has not yet been clearly revealed how these important microvilli are formed and by what mechanisms they are regulated. To address this, the research team focused on the GTPase protein "Cdc42," which regulates the cell cytoskeleton. They confirmed that if the sensory protrusions of T cells, the microvilli that function like tentacles, do not form properly during the differentiation and maturation of immune cells in the small organ known as the thymus, the overall immune response can be disrupted.

In fact, during the "double-positive (DP)" stage of T cell maturation in the thymus, when the expression of the Cdc42 gene decreases, microvilli fail to form properly, resulting in shorter length and a significant reduction in number.

Observation of microvilli and TCR microclusters in T cells of Cdc42 conditional knockout mice.

To analyze the role of the Cdc42 protein more precisely, the research team conducted experiments using ▲a genetically modified mouse model in which the Cdc42 gene was selectively deleted and ▲a mouse model treated with CASIN, an inhibitor that specifically targets the Cdc42 protein.

As a result, T cells deficient in Cdc42 showed a marked decrease in both the length and number of microvilli, as well as abnormalities in the formation of T cell receptor (TCR) microclusters and immune synapses, both of which are essential for antigen recognition.

Ultimately, it was confirmed that T cells could not effectively recognize external antigens, resulting in an overall weakening of the immune response. This provides molecular-level evidence that Cdc42 plays a critical role in the formation of T cell microvilli and the stable performance of immune functions.

The research team explained, "T cells lacking Cdc42 lose the directionality and precision of immune responses, as they cannot properly detect external signals, much like insects that have lost their antennae."

This study was conducted using advanced high-resolution imaging technologies, including electron microscopy, confocal microscopy, total internal reflection fluorescence microscopy, and multiphoton fluorescence microscopy. Through these methods, the team was able to observe the three-dimensional and multifaceted relationship between the ultrastructural changes of microvilli and immune function, offering a new molecular immunological interpretation linking T cell structure and function.

This achievement is being evaluated as a paradigm-shifting study in immunology, encompassing both the structure and function of T cells. Based on these findings, the research team has opened up the possibility of developing next-generation immunotherapies applicable to various immune-related diseases, including autoimmune diseases, infectious diseases, and cancer.

Professor Jeon Changdeok stated, "Through this study, we have elucidated the mechanisms of formation and functional regulation of T cell microvilli at the molecular level," adding, "Based on this, we expect to take a step closer to developing next-generation immune anticancer drugs utilizing 'immune synaptosomes' derived from microvilli."

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