Blog

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.

One of the biggest challenges in cancer treatment is that certain cancers reappear after chemotherapy-and an aggressive type of blood cancer called acute myeloid leukemia (AML) is notorious for this. Now, new research from The Jackson Laboratory (JAX) points to a previously unknown molecular mechanism behind that chemoresistance, and a way to potentially disarm it.

In findings newly published in Blood Cancer Discovery, a team led by JAX assistant professor Eric Wang reports on the role of a protein called RUNX1C in this mechanism. A little-known variation, or “isoform” of a gene called RUNX1, the RUNX1C protein helps regulate how blood cells resist chemotherapy.

By studying data from AML patients from before they received chemotherapy and again after their cancer returned, the team found that in many cases a chemical tag known as DNA methylation had appeared in a section of the genome that normally controls the RUNX1 gene. That small change flipped a genetic switch, forcing cancer cells to make more of the RUNX1C isoform, activating a mechanism that made them far better at withstanding chemotherapy.

Specifically, RUNX1C turned on a gene called BTG2. This interfered with the cells’ RNA, slowing down cell activity and pushing leukemia cells into a dormant or quiescent state where they stop dividing. In this state, cancer cells effectively hide from chemotherapy, which works best when cancer cells are actively dividing. In other words, dormant cancer cells go unnoticed and can “wake up” after treatment.

“The problem right now is that there is no treatment for patients who relapse, and that’s why our study is so important-not just to understand what isoforms or genes mediate resistance but to understand how we can target them in the future,” Wang said. “Scientists have done extensive RNA isoform analysis but not in the context of AML relapse. Our study is a good resource to show that in addition to genes, RNA isoforms are also very important in mediating chemoresistance.”

If a safe and targeted way can be developed to block RUNX1C in patients, it could prevent cancer cells from slipping into quiescence, making chemotherapy more effective and reducing the risk of relapse, Wang said. The team tested two RNA-targeting tools against RUNX1C in AML models both in cultured cells and in mice.

Pairing RUNX1C inhibition with standard chemotherapy significantly improved the drugs’ ability to kill leukemia cells. Without the isoform’s influence, the dormant cancer cells “woke up” and started dividing again-precisely the state when chemotherapy is most effective.

Dr. Cuijuan Han, the lead author of the study, explained, “We demonstrated that overexpressing this isoform confers resistance to many of the chemotherapy treatments used for AML. We’ve done experiments to do the inverse, where we also knocked out the isoform and see that it confers sensitivity.”

Wang’s lab is collaborating with other organizations to continue using these RNA-targeting tools, known as antisense oligonucleotides (ASOs), which can bind to RNA and block it from making certain proteins like RNA isoforms. If further studies confirm the results, targeting RUNX1C with ASO technology could become a powerful tool in the fight against AML, Wang said. While this technology is in experimental stages for rare neurological diseases at JAX, it hasn’t been widely applied to AML or most other cancers.

“Our study provides a proof of principle that knocking down isoforms with the right technology could enhance or even overcome chemoresistance,” Wang said. “Although our lab does not focus on other cancers, applying this concept to other cancers may provide rationale to focus on whether targeting RNA isoforms can modulate drug response with different drugs and different cancers.”

Eric Wang was supported by The Jackson Laboratory Cancer Center (JAXCC) New Investigator Award (P30CA034196), JAX start-up funds, JAX Cancer Center Fast Forward Award, Leukemia Research Foundation (LRF), and Butler Family Foundation. 

Neurons in the gut produce a molecule that plays a pivotal role in shaping the gut’s immune response during and after inflammation, according to a new study by Weill Cornell Medicine investigators. The findings suggest that targeting these neurons and the molecules they produce could open the door to new treatments for inflammatory bowel disease and other disorders driven by gut inflammation.

Hundreds of millions of neurons make up the enteric nervous system, the “second brain” of the body, where they orchestrate essential functions of the gut such as moving food through the intestines, nutrient absorption and blood flow. While this system is known for regulating these fundamental processes, its role in controlling intestinal inflammatory responses has remained far less clear.

In their study, reported August 15 in Nature Immunology, the investigators focused on group 2 innate lymphoid cells (ILC2s), immune cells that reside within the linings of the gut. Their previous work revealed that ILC2s are a major source of a tissue-healing growth factor called amphiregulin and have the capacity to receive neuronal signals that modulate their function and can impact disease progression and recovery. In the new study, they demonstrated that the tissue-protective function of ILC2s depends on production of a molecule called adrenomedullin 2 (ADM2) from the enteric nervous system; administering the molecule expanded this group of ILC2s and provided therapeutic benefit in a preclinical model of inflammatory bowel disease, whereas loss of ADM2 signaling exacerbated disease due to the lack of these protective cells.

The enteric nervous system has long been neglected when thinking of how we can resolve detrimental intestinal inflammation. Our work suggests there may be a previously unknown neuro-immune mechanism driving intestinal healing responses.”

Dr. Jazib Uddin, lead author, an NIH Ruth L. Kirschstein postdoctoral fellow at Weill Cornell Medicine

Additionally, the investigators performed translational patient-based studies by analyzing human tissue and blood samples from Weill Cornell Medicine’s Jill Roberts Institute for Research in Inflammatory Bowel Disease Live Cell Bank. This analysis revealed that patients with inflammatory bowel disease had elevated expression of ADM2 compared with control individuals and found that human ILC2s stimulated with ADM2 directly promoted production of tissue-protective amphiregulin. These findings indicate that the immune-nervous system communication identified in mice is also present in humans, highlighting the enteric nervous system as a promising therapeutic target for inflammatory bowel disease.

“The findings of this current study allow new insights into how the immune and nervous systems ‘speak’ to each other and coordinate complex processes, including tissue inflammation and repair, and offer the potential for new therapies targeting these neuro-immune interactions,” said senior author Dr. David Artis, director of the Jill Roberts Institute for Research in Inflammatory Bowel Disease and the Michael Kors Professor in Immunology at Weill Cornell Medicine and co-director of the Allen Discovery Center for Neuro-immune Interaction.