Rheumatoid arthritis (RA) is an autoimmune disease that affects millions worldwide and can have a devastating impact on patients’ lives. Yet, about one in three patients respond poorly to existing treatments. Researchers at Kyoto University have shed new light on this challenge by discovering that peripheral helper T cells (Tph cells), a key type of immune cell involved in RA, exist in two forms: stem-like Tph cells and effector Tph cells. The stem-like Tph cells reside in immune “hubs” called tertiary lymphoid structures within inflamed joints, where they multiply and activate B cells. Some of these then become effector Tph cells that leave the hubs and cause inflammation. This continuous supply of effector Tph cells may explain why inflammation persists in some patients despite treatment. Targeting the stem-like Tph cells at the source could offer a new therapeutic strategy, bringing hope for more effective symptom relief and improved quality of life for patients living with RA.
This research is led by Yuki Masuo, a doctoral student at the Graduate School of Medicine, Kyoto University; Associate Professor Hiroyuki Yoshitomi of the Department of Immunology (also Associate Investigator at WPI-ASHBi), Graduate School of Medicine, Kyoto University; and Professor Hideki Ueno, Vice Director and Principal Investigator at WPI-ASHBi (also Professor at the Department of Immunology, Graduate School of Medicine, Kyoto University, and Director of the Kyoto University Immunological Monitoring Center, KIC). These findings will be published online in Science Immunology on August 15, 2025, at 2:00 PM local time (August 16 at 3:00 AM JST).
Background
Rheumatoid arthritis (RA) is one of the most common autoimmune diseases, affecting approximately 18 million people worldwide. It occurs when the immune system mistakenly attacks the joints, leading to chronic inflammation, pain, swelling, and joint damage. While treatments have improved in recent years, about 30% of patients still respond poorly to existing therapies. This underscores the need to better understand the disease’s underlying immune mechanisms in order to develop more effective treatments for these patients.
Many types of immune cells are involved in the disease mechanism of RA. Among them, helper T cells act as the “commanders” of the immune system, recognizing threats and directing the activity of other immune cells. A recent study from Kyoto University found that a subset of helper T cells called peripheral helper T (Tph) cells builds up in in the joints of patients with RA and contributes to inflammation. However, exactly where these Tph cells are located and activated in the joint and how they fuel the inflammation have not been fully understood.
Building on their earlier work, the research team analyzed immune cells from inflamed joint tissue and blood of people with RA using a comprehensive approach called multi-omics, which combines different types of biological data to get a full picture of the dynamic behavior of Tph cells in RA-affected joint tissue.
Key Findings
Using single-cell RNA sequencing, the team discovered two distinct types of peripheral helper T (Tph) cells within inflamed joint tissue: stem-like Tph cells, which can self-renew while maintaining their identity, and effector Tph cells, which are more activated but rarely divide. Over time, stem-like Tph cells can mature into effector Tph cells, but not the other way around.
The researchers then used a method called spatial transcriptomics to see exactly where Tph cells are within the inflamed joint. This method shows not only the location of Tph cells but also how they are arranged relative to other immune and tissue cells (such as B cells, macrophages, and fibroblasts) and to immune “hubs” called tertiary lymphoid structures (TLSs). The results revealed that most stem-like Tph cells live inside these immune hubs, where they interact closely with B cells. By growing stem-like Tph cells and B cells together in lab, the researchers found that this interaction not only helps stem-like Tph cells develop into effector Tph cells but also activate B cells. On the other hand, effector Tph cells are found outside the hubs, where they interact with other immune cells such as macrophages and cytotoxic (killer) T cells that promote inflammation.
Overall, this study revealed the presence of two types of Tph cells with different roles in inflamed joint tissue. Stem-like Tph cells live within TLSs, where they self-renew and help activate B cells. Some of them mature into effector Tph cells, which then leave TLSs and cause inflammation.
Future Perspectives
“Using cutting-edge analytical techniques that have only recently become available, we have uncovered a new aspect of the immune response at the sites of joint damage in RA,” said first author Yuki Masuo. “Because stem-like Tph cells can both self-renew and differentiate, they may represent a root cause of the disease.”
In patients with RA who respond poorly to treatment, the activity of stem-like Tph cells may help explain their persistent symptoms. Further research into the functions of these cells could lead to novel targeted therapies, potentially improving symptom relief and enhancing quality of life for these patients.
KYOTO, Japan – August 15th 2025
Glossary
Autoimmune disease: A disorder where the immune system, which normally protects the body, mistakenly attacks healthy cells, causing inflammation and tissue damage.
Stem cells: Specialized cells with the ability to self-renew and transform into other cell types.
Differentiation: The process by which cells mature into forms with specific functions.
Helper T Cells: A type of white blood cell that acts as the "commander" of the immune system. They play a key role in directing immune responses by helping B cells produce antibodies and by supporting the activation of other immune cells in response to infections or foreign substances.
Peripheral Helper T Cells (Tph cells): A type of helper T cell found in inflamed tissues. They help form structures that support a long-lasting immune response.
Spatial transcriptomics: A technique that shows where different genes are active in a tissue slice. It helps scientists see which cell types are in specific spots and how they interact with each other
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About Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University
What key biological traits make us ‘human’, and how can knowing these lead us to better cures for disease? ASHBi investigates the core concepts of human biology with a particular focus on genome regulation and disease modeling, creating a foundation of knowledge for developing innovative and unique human-centric therapies.
About the World Premier International Research Center Initiative (WPI)
The WPI program was launched in 2007 by Japan's Ministry of Education, Culture, Sports, Science and Technology (MEXT) to foster globally visible research centers boasting the highest standards and outstanding research environments. Numbering more than a dozen and operating at institutions throughout the country, these centers are given a high degree of autonomy, allowing them to engage in innovative modes of management and research. The program is administered by the Japan Society for the Promotion of Science (JSPS).
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